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What is the chance a given gene will end up in a given gamete?

What is the chance a given gene will end up in a given gamete?


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Let us say a germ cell had a desired allele. This germ cell was replicated during interphase so that it had two of the desired allele. It then underwent meiosis.

My question then is, what is the chance a given allele will end up in a given gamete that will be involved in conception?

Firstly, there is a 50% chance a chromosome will be assigned to a given daughter cell. This is because of independent assortment. In addition, cross over occurs at chiasmata. Lets assume then that there was a 50% chance that an allele will be crossed over (although this probability may be far from true)

The process during meiosis is that cross-over occurs first. We have two desired alleles, each on one of two pairs of chromatid attached to each other. There is 50% chance for a given allele to cross over. For example, the chance for both desired alleles to cross over is 1/4 (1/2 x 1/2), the chance only one will cross over is 2/4 (since either of the two desired alleles can cross over).

Then there is the first independent assortment during meiosis I which produces the desired daughter cell. In this case there is a 50% chance that a given chromatid pair (containing the desired allele) will be assigned to the desired daughter cell. However, in the case where a desired allele is found in both homologs (2/4 of a chance), then the chance that at least one desired allele will be in the daughter cell is 100%.

Finally, during meiosis II, another independent assortment occurs which produces the desired gamete. The same rule applies with a 50% chance a given allele will be assigned to a given cell (in this case the gamete). However, if the desired daughter cell contains two of the desired alleles, then there is a 100% chance that the cell will have the desired allele.

In conclusion, the chance I estimated that the gamete will have at least one desired allele is 50%. Although, I'm not sure if this is correct. Anyone mind confirming this.


A cell contains two haplotypes (or two set of all chromosomes). One haplotype inherited from the mother, one from the father. A haploid cell, resulting from meiosis, will receive either the maternal (or grandmother if you prefer) or paternal (or grandfather if you prefer) haplotype. It cannot receive anything else. Hence the probably must be 0.5 (or 50%).

Note that you are using the term "gene" incorrectly. You should use the term "allele" instead. And while you are improving your genetic vocabulary you should also check the term "locus". Also, the term "desired gene" is never used. We talk about "beneficial allele" or "detrimental allele".


You are making this too complicated. There is a 50% of any particular allele ending up in a gamete. The end.


What is the chance a given gene will end up in a given gamete? - Biology

Mendel formed the Laws of Heredity (the Law of Segregation and the Law of Independent Assortment) from his pea plant experiments.

Learning Objectives

Discuss the methods Mendel utilized in his research that led to his success in understanding the process of inheritance

Key Takeaways

Key Points

  • By crossing purple and white pea plants, Mendel found the offspring were purple rather than mixed, indicating one color was dominant over the other.
  • Mendel’s Law of Segregation states individuals possess two alleles and a parent passes only one allele to his/her offspring.
  • Mendel’s Law of Independent Assortment states the inheritance of one pair of factors ( genes ) is independent of the inheritance of the other pair.
  • If the two alleles are identical, the individual is called homozygous for the trait if the two alleles are different, the individual is called heterozygous.
  • Mendel cross-bred dihybrids and found that traits were inherited independently of each other.

Key Terms

  • homozygous: of an organism in which both copies of a given gene have the same allele
  • heterozygous: of an organism which has two different alleles of a given gene
  • allele: one of a number of alternative forms of the same gene occupying a given position on a chromosome

Introduction

Mendelian inheritance (or Mendelian genetics or Mendelism) is a set of primary tenets relating to the transmission of hereditary characteristics from parent organisms to their children it underlies much of genetics. The tenets were initially derived from the work of Gregor Mendel published in 1865 and 1866, which was “re-discovered” in 1900 they were initially very controversial, but they soon became the core of classical genetics.

The laws of inheritance were derived by Gregor Mendel, a 19th century monk conducting hybridization experiments in garden peas (Pisum sativum). Between 1856 and 1863, he cultivated and tested some 28,000 pea plants. From these experiments, he deduced two generalizations that later became known as Mendel’s Laws of Heredity or Mendelian inheritance. He described these laws in a two part paper, “Experiments on Plant Hybridization”, which was published in 1866.

Mendel’s Laws

Mendel discovered that by crossing true-breeding white flower and true-breeding purple flower plants, the result was a hybrid offspring. Rather than being a mix of the two colors, the offspring was purple flowered. He then conceived the idea of heredity units, which he called “factors”, one of which is a recessive characteristic and the other dominant. Mendel said that factors, later called genes, normally occur in pairs in ordinary body cells, yet segregate during the formation of sex cells. Each member of the pair becomes part of the separate sex cell. The dominant gene, such as the purple flower in Mendel’s plants, will hide the recessive gene, the white flower. After Mendel self-fertilized the F1 generation and obtained an F2 generation with a 3:1 ratio, he correctly theorized that genes can be paired in three different ways for each trait: AA, aa, and Aa. The capital A represents the dominant factor while the lowercase a represents the recessive.

Mendel’s Pea Plants: In one of his experiments on inheritance patterns, Mendel crossed plants that were true-breeding for violet flower color with plants true-breeding for white flower color (the P generation). The resulting hybrids in the F1 generation all had violet flowers. In the F2 generation, approximately three-quarters of the plants had violet flowers, and one-quarter had white flowers.

Mendel stated that each individual has two alleles for each trait, one from each parent. Thus, he formed the “first rule”, the Law of Segregation, which states individuals possess two alleles and a parent passes only one allele to his/her offspring. One allele is given by the female parent and the other is given by the male parent. The two factors may or may not contain the same information. If the two alleles are identical, the individual is called homozygous for the trait. If the two alleles are different, the individual is called heterozygous. The presence of an allele does not promise that the trait will be expressed in the individual that possesses it. In heterozygous individuals, the only allele that is expressed is the dominant. The recessive allele is present, but its expression is hidden. The genotype of an individual is made up of the many alleles it possesses. An individual’s physical appearance, or phenotype, is determined by its alleles as well as by its environment.

Mendel also analyzed the pattern of inheritance of seven pairs of contrasting traits in the domestic pea plant. He did this by cross-breeding dihybrids that is, plants that were heterozygous for the alleles controlling two different traits. Mendel then crossed these dihybrids. If it is inevitable that round seeds must always be yellow and wrinkled seeds must be green, then he would have expected that this would produce a typical monohybrid cross: 75 percent round-yellow 25 percent wrinkled-green. But, in fact, his mating generated seeds that showed all possible combinations of the color and texture traits. He found 9/16 of the offspring were round-yellow, 3/16 were round-green, 3/16 were wrinkled-yellow, and 1/16 were wrinkled-green. Finding in every case that each of his seven traits was inherited independently of the others, he formed his “second rule”, the Law of Independent Assortment, which states the inheritance of one pair of factors (genes) is independent of the inheritance of the other pair. Today we know that this rule holds only if the genes are on separate chromosomes


Many of the traits an individual has, from eye color to the risk of having certain diseases, are passed from parents to their children via their genes. In diploid organisms, such as humans, most cells contain two copies – or alleles – of every gene. The exceptions to this rule are gametes (that is, sperm and egg cells), which contain just one allele. According to Mendel’s famous law of segregation, half of the gametes will carry one allele for a given gene, and the other half will carry the other allele. Thus, both of the mother’s alleles have an equal chance of being passed on to her children, and likewise for the father’s alleles.

However, some alleles defy Mendel’s law and can increase their chances of being transmitted to the next generation by killing gametes that do not share the same alleles (Burt and Trivers, 2006). Genes harboring alleles that behave in this way have been identified in plants, fungi and animals – including humans – and are called by various names, including selfish drivers, gamete killers and spore killers.

There are many types of selfish drivers and much remains unclear about how they work, though they can generally be distinguished by the way they destroy other cells. In the ‘poison-antidote’ model, the selfish driver produces a poison that destroys all gametes unless an antidote is there to protect them from the effects of the poison (Figure 1A and B). In the ‘killer-target’ model, the selfish driver produces a poison that kills gametes that carry a specific target (Figure 1C).

The poison-antidote and killer-target models of selfish drivers.

In both models, a particular allele has an increased chance of being passed on to the next generation because it produces a toxin to kill gametes that do not carry it. (A, B) In the poison-antidote model, cells produce a toxin (shown as skull-and-crossbones) that can be neutralized by an antidote (shown as a pill) the alleles that do not code for either are shown in gray. In the single-gene model (A) the same gene codes for both the poison and the antidote through alternative transcription. Nuckolls et al. show that the gene wtf4 is a selfish driver in Schizosaccharomyces yeasts. Hu et al. show that two other genes in the wtf family (cw9 and cw27) are also selfish drivers. In the two-gene model (B) different genes produce the poison and antidote, as in the fungus Neurospora (Hammond et al., 2012). (C) In the killer-target model, the toxin only destroys cells that contain alleles with a specific target marker (shown here by concentric black circles). This is the case in Drosophila, where the segregation distortion (Sd) allele acts by killing gametes that contain a sensitive Responder (Rsp s ) marker (Larracuente and Presgraves, 2012).

Aiming to understand how selfish drivers have evolved and work, two research groups – one led by Sarah Zanders and Harmit Malik, the other by Li-Lin Du – turned to two species of fission yeast, Schizosaccharomyces kambucha and S. pombe. These two species are genetically nearly identical, and some researchers do not even consider them as separate species (Rhind et al., 2011), but hybrids between the two are often sterile. In previous studies, Zanders and co-workers discovered that S. kambucha has at least three selfish drivers that cause infertility in the hybrids (Zanders et al., 2014).

To unravel the genetic identity of these selfish drivers in yeast, Zanders, Malik and co-workers at the Stowers Institute for Medical Research, the Fred Hutchinson Cancer Research Center and the University of Kansas Medical Center – including Nicole Nuckolls and Maria Angelica Bravo Núñez as joint first authors – isolated a region on a chromosome that caused selfish drive (Nuckolls et al., 2017). Within this region, they found a selfish-driver gene called wtf4 – a member of a large and cheekily-named gene family – which creates both a poison and an antidote.

To explore the underlying mechanisms in more detail, Nuckolls et al. created fluorescent versions of the poison and the antidote and mapped their location inside and around the gametes. These elegant experiments showed that wtf4’s poison can leave their originating cells and cross into surrounding cells while the antidote remains trapped inside the cells that produce it.

In an independent study, Du and co-workers at the National Institute of Biological Sciences in Beijing – including Wen Hu as first author – identified two other genes from the wtf gene family, named cw9 and cw27, as selfish drivers that also employ the poison-antidote model in crosses between different strains of S. pombe (Hu et al., 2017). They found that mutant diploid strains missing both copies of either cw9 or cw27 survived more than strains missing only one copy of the gene, indicating that both genes are selfish drivers. When they created diploid mutants missing a copy of cw9 and cw27, the yeast strains survived even less compared to strains missing a copy of only one of the two genes. This suggests that the two genes do not rescue each other and that they act independently to drive survival.

By identifying several genes within the same family that can kill cells that are different, and by exploring their mode of action, the work of these two groups enriches our understanding of the genes that break Mendel’s acclaimed genetic law. Future work in this area will help us to understand the impact of selfish elements on genetic diversity and may lead to a deeper understanding of how these mechanisms affect conditions such as infertility in species as diverse as plants, fungi and animals – including humans.


F2: hybrids of hybrids

After this discovery, Mendel grew out the F1 generation (the hybrids of the pure lines) and then repeated the same cross pollination, generating new seeds. These seeds formed the second filial or F2 generation, which can be thought of as hybrids of the original hybrids. To his surprise, not only did the dominant genotype (round seeds) emerge in the F2 generation, but also the recessive phenotype (wrinkly seeds). More precisely, he collected 5474 round seeds and 1850 wrinkly seeds, or a 2.96 dominant to 1 recessive ratio, approximately 3:1.

Mendel then repeated the same experiment for a variety of other traits with his peas, such as: seed color, pod color, flower color, and pod shape. From his original experiment, he predicted that in each of the physical characteristics one phenotype would dominate in the F1 generation, masking the recessive phenotype. From his seed shape experiment, he also predicted an approximate 3:1 ratio of dominant to recessive phenotypes in the F2 generation. And that is exactly what he found. Let’s use seed color as an example. Mendel crossed pure line yellow seeded and green seeded plants. Seeds from that cross (the F1 generation) were all yellow, indicating the dominant phenotype. After growing those seeds out and crossing the hybrids, he counted the F2 seeds: 6022 yellow and 2001 green, a 3.01:1 ratio. He found a similar ratio for other characteristics in the F2 generation: pod shape was 2.95 inflated to 1 constricted, pod color was 2.82 green to 1 yellow, and flower color was 3.15 purple to 1 white – all approximately 3:1.


Basic Concepts in Molecular Biology

This chapter introduces the fundamental concepts in molecular biology that underlie the principles of genetics and inheritance. It begins with a discussion of the way that genetic material is organized into genes and chromosomes and the mechanisms by which these are transmitted to the next generation. This is followed by an explanation of the molecular nature of genes and the processes of DNA replication and gene expression. The flow of information from DNA to RNA to protein is described along with the consequences of mutations on this system. Finally, a brief survey of current genetic technologies is presented, including the burgeoning field of genomics. This chapter provides the foundational concepts on which subsequent chapters are built.

CHROMOSOMES

The term chromosome is derived from the Greek words for color ( chroma ) and body ( soma ) as chromosomes were first observed as colored threads inside the nucleus of stained cells by scientists in the 1800s. These thread-like structures are present in the nucleus of all cells and are the basic units of heredity that are passed from parents to their offspring.

Chromosomes are composed of a single molecule (double strand) of DNA, which is wrapped around histone proteins (Figure 2.1). The association of DNA with histone proteins is known as chromatin . Chromosomes exist in the cell in one of two forms, condensed (closed) or relaxed (open). For most of the time, the DNA in chromosomes is only loosely wound around histone proteins so that the genes on the chromosomes are accessible to the transcriptional machinery of the cell. In this form, chromosomes exist as long slender threads that are not visible under a light microscope. Only when a cell is getting ready to divide does the DNA become compacted to take on the characteristic shape and form of a chromosome.

Before a cell divides it makes a duplicate copy of each chromosome both chromosome copies remain temporarily stuck together, with each individual chromosome referred to as a chromatid (Figure 2.2). During cell division the DNA of both chromatids are wound tightly around histone proteins so that it forms a short tight bundle. This makes it easier for the cell to move the chromosomes around the cell, and is analogous to taking multiple lengths of yarn and winding them up into individual balls for ease of handling. In this condensed form, chromosomes are visible under the light microscope, and each individual chromosome can be identified on the basis of its size and the pattern of bands created when the chromosomes are stained with Giemsa (G banding). During the time that chromosomes are in this condensed form, the DNA is so tightly wound around the histones that transcription cannot take place. For this reason, as soon as nuclear division is complete, the chromosomes rapidly decondense so that the DNA is accessible once more and can be used by the cell to direct the production of proteins.

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FIGURE 2.1. The association of DNA and histone proteins to form chromatin.

In the condensed state, certain features of a chromosome become visible. A constriction in the chromosome identifies the chromosome centromere , which holds the two chromatids together. During nuclear division ( mitosis or meiosis ), spindle fibers attach to specialized regions of the centromere known as kinetochores to move the chromosomes around the cell. The ends of each chromosome are called telomeres , which are made up of short DNA sequences that are repeated over many times and do not code for proteins. Telomeres have a protective function for the chromosome, and shortening of telomeres has been linked to aging and cancer.

Humans have 23 pairs of different chromosomes in a somatic (nonsex) cell, with one of each pair being inherited from each parent. Twenty-two of these chromosome pairs do not play a role in sex determination and are referred to as autosomes . The remaining pair are called the sex chromosomes or X and Y chromosomes, because these determine the sex of an individual. In humans, sex is determined by the presence or absence of the Y sex chromosome, with females having two X chromosomes and males having one X and one Y chromosome. In the absence of a Y chromosome, embryonic development proceeds along the default female pathway. In the presence of a Y chromosome, development is switched to that of male by a transcription factor that is encoded by the sex-determining region Y ( SRY ) gene, which is found only on the Y chromosome. Because somatic cells contain two copies of each chromosome type, they are referred to being diploid , and their chromosome number is denoted as 2n . Gametes , which are cells specialized for fertilization (sperm and oocytes), have only one of each chromosome and are said to be haploid and are given the n designation. The fusion of haploid male and female gametes during fertilization restores the diploid number of chromosomes (46) to the zygote, with one maternally derived chromosome and one paternally derived chromosome for each pair.

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FIGURE 2.2. The structure of a duplicated chromosome.

CELL DIVISION

Cell Cycle

Cells preparing to divide progress through a series of phases, which collectively are known as the cell cycle (Figure 2.3). The cell cycle could be considered the “life cycle” of the cell however, only cells that have been given “permission” to divide complete the cell cycle, and nondividing cells remain in the first phase of the cell cycle indefinitely, which is referred to as the resting phase or G 0 .

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FIGURE 2.3. The four phases of the cell cycle.

The first phase of the cell cycle, called the gap 1 (G 1 ) phase, occurs immediately following cell division. When the parental cell divides in half to create two daughter cells, these are initially half the size of the parental cell with only half the number of organelles. The first task for this newly created cell is to increase its size and synthesize additional organelles. Therefore, the G 1 phase is considered to be a period of growth. Once a cell has reached its full size and capacity it does not automatically proceed to cell division. There are strict controls on which cells are allowed to divide, and division is only permitted if there is a need for more cells for the purposes of growth, repair, or regeneration. Therefore, there are a host of cell cycle controls that prevent a cell from leaving G 1 and proceeding with division. These are enforced by proteins, such as cyclins , that enforce cell cycle checkpoints , the maintenance of G 1 state, and prevent cells from leaving G 1 and progressing through the cell cycle. Mutation of one or more of these genes results in loss of cell cycle control, and cells progress through the cell cycle and divide in an uncontrolled way, leading to cancer. The mitotic index is a measurement of cell proliferation that measures the ratio of mitotic (dividing) cells to nondividing cells within a population. An elevated mitotic index can be indicative of the presence of cancerous cells that have lost cell cycle control.

When cell division is required, a chemical signal will be received by the cell, which leads to the removal of G 1 checkpoint controls, and the cell then enters the second phase of the cell cycle, the S phase . During this phase of the cell cycle, DNA synthesis occurs, and all of the chromosomes are replicated, leading to a doubling of the DNA content of a cell. There is no checkpoint at the end of the S phase rather, cells proceed directly into the gap 2 (G 2 ) phase, which is another period of growth. During the G 2 phase, the cell prepares for nuclear and cell division, by synthesizing the proteins that will be required to drive this process. The gap phases of the 13 cell cycle (G 1 and G 2 ) were named by early researchers studying the cell cycle by observing visible changes under the microscope. In contrast to S and M phases, the processes taking place during G 1 and G 2 do not create any visible changes in cellular morphology, leading scientists to name them “gap” phases to reflect what they incorrectly thought of as periods of inactivity in the cell.

At the end of the G 2 phase there is another cell cycle checkpoint, and cells can only progress to the next phase of the cell cycle when their DNA has been checked and found to be undamaged. If any DNA damage is found, it must be repaired before cells can proceed any further. Cells that pass the G 2 checkpoint proceed into the M phase , which is where nuclear division and eventually cytokinesis (cell division) takes place. The G 1 , S, and G 2 phases are known collectively as interphase , to reflect that these are the phases leading up to nuclear and cell division.

The ploidy status, which is the number of sets of chromosomes of a cell, is determined by the method of nuclear division that is used to create the two nuclei during the M phase of the cell cycle, as a precursor to cytokinesis. Nuclear division occurs during the M phase of the cell cycle by one of two methods, mitosis or meiosis, depending on the function of the cell.

Mitosis

Somatic cells do not participate in reproduction and are therefore diploid, having two copies of each chromosome, referred to as homologous chromosomes . During the S phase of the cell cycle, a somatic cell makes a copy of all of its chromosomes this double complement of chromosomes must become organized into two separate nuclei, each containing a complete set of chromosomes, before cell division can occur. Somatic cells achieve this through the process of mitosis, a method of nuclear division which, in humans, separates a set of 46 chromosomes into each of two nuclei. Mitosis is followed by cell division to generate two diploid daughter cells that have maintained the chromosome number of 46. This method of nuclear division is used by all dividing cells except gametes, for the purpose of growth, regeneration, and repair, and generates daughter cells that are genetically identical to the original parental cell. Organisms that reproduce asexually also divide by mitosis, leading to offspring that are identical, genetic clones of the parent.

Mitosis begins with all of the chromosomes being in their duplicated state, having been replicated during the S phase. Both of the chromosome duplicates, known as sister chromatids , remain fastened together at the centromere. The goal of mitosis is to pull apart these chromosome copies and move them into separate nuclei. Mitosis is divided into five stages, the first of which is prophase (Figure 2.4). During this phase, the chromosomes condense to become shorter and thicker in preparation for being moved around the cell. At the beginning of prophase, stained chromosomes are barely visible as thin threads however, by the end of prophase the chromosomes have condensed to such an extent that they are then visible as the shapes that we commonly associate with chromosomes. The end of prophase is marked by the disappearance of the nuclear membrane to allow access of the spindle fibers to each chromosome. Metaphase is the most characteristic stage of mitosis, as this is the phase where spindle fibers move the chromosomes so that they are lined up along the center of the cell ( metaphase plate ). This stage of the cell cycle is used for preparing karyotypes (images of individual chromosomes for the purpose of identifying abnormalities in chromosome number or structure). When preparing cells for karyotyping, they are treated with a chemical inhibitor, which prevents the cells from leaving metaphase. This ensures that the chromosomes are in their most condensed state and therefore most highly visible under a light microscope. Before the cell proceeds to the next phase of mitosis, a cell cycle checkpoint is encountered, which ensures that all spindle fibers are attached to the chromosome centromeres. This is very important because errors at this point could lead to incorrect separation of duplicated chromosomes ( nondisjunction ), leading to conditions of aneuploidy (abnormal chromosome number). (For a more detailed description of aneuploidy, see Chapter 4.) Once this cell checkpoint has been verified, cells enter anaphase , which is when the spindle fibers abruptly shorten, pulling duplicated chromosomes apart and toward opposite poles of the cell. When adequate separation of the chromosome pairs has been achieved, the nuclear membranes quickly re-form around each complete set of chromosomes in the last phase of mitosis known as telophase . At this stage the chromosomes rapidly decondense, allowing access to the DNA for the resumption of transcription. For a very brief period, the cell has two nuclei however, as soon as telophase is complete, the cell quickly divides its cell contents in half to form two cells. At this point, the cell cycle is complete and each newly created daughter cell enters the G 1 phase.

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FIGURE 2.4. The four phases of mitosis, which achieves nuclear division in somatic cells.

15 Meiosis

Gametes, which are cells specialized for reproduction (sperm and eggs), do not use mitosis for nuclear division because a haploid nucleus must be generated during cell division. In order to generate two haploid nuclei with only one of each chromosome type, the nucleus must divide using meiosis. Meiosis is a form of nuclear division that includes two rounds, resulting in the formation of four haploid cells. The first nuclear division, meiosis I , separates each pair of homologous chromosomes to generate two haploid nuclei, and for this reason is referred to as a reductive division . Although the first round of meiosis has generated two haploid nuclei, each chromosome is still in the duplicated state with the two sister chromatids connected at the centromere. The second round of meiotic nuclear division, meiosis II , is similar to mitosis in that it functions to separate duplicated sister chromatids, creating haploid nuclei, each with a set of unduplicated chromosomes this is an equational division . Both meiosis “I” and “II” are divided into the same four stages of prophase, metaphase, anaphase, and telophase as mitosis (Figure 2.5). A phase is identified as being from meiosis I or II by the use of the Roman numeral I or II. For example, metaphase I indicates that this is metaphase from meiosis I and metaphase II indicates metaphase of meiosis II the absence of a number indicates that this is a phase of mitosis (e.g., metaphase). A comparison of mitosis and meiosis is shown in Table 2.1.

FIGURE 2.5. The four phases of meiosis, which create haploid nuclei during nuclear division of germ cells.


Abstract

To characterize the role of the circadian clock in mouse physiology and behavior, we used RNA-seq and DNA arrays to quantify the transcriptomes of 12 mouse organs over time. We found 43% of all protein coding genes showed circadian rhythms in transcription somewhere in the body, largely in an organ-specific manner. In most organs, we noticed the expression of many oscillating genes peaked during transcriptional “rush hours” preceding dawn and dusk. Looking at the genomic landscape of rhythmic genes, we saw that they clustered together, were longer, and had more spliceforms than nonoscillating genes. Systems-level analysis revealed intricate rhythmic orchestration of gene pathways throughout the body. We also found oscillations in the expression of more than 1,000 known and novel noncoding RNAs (ncRNAs). Supporting their potential role in mediating clock function, ncRNAs conserved between mouse and human showed rhythmic expression in similar proportions as protein coding genes. Importantly, we also found that the majority of best-selling drugs and World Health Organization essential medicines directly target the products of rhythmic genes. Many of these drugs have short half-lives and may benefit from timed dosage. In sum, this study highlights critical, systemic, and surprising roles of the mammalian circadian clock and provides a blueprint for advancement in chronotherapy.

Circadian rhythms are endogenous 24-h oscillations in behavior and biological processes found in all kingdoms of life. This internal clock allows an organism to adapt its physiology in anticipation of transitions between night and day. The circadian clock drives oscillations in a diverse set of biological processes, including sleep, locomotor activity, blood pressure, body temperature, and blood hormone levels (1, 2). Disruption of normal circadian rhythms leads to clinically relevant disorders including neurodegeneration and metabolic disorders (3, 4). In mammals, the molecular basis for these physiological rhythms arises from the interactions between two transcriptional/translational feedback loops (reviewed in ref. 5). Many members of the core clock regulate the expression of other transcripts. These clock-controlled genes mediate the molecular clock’s effect on downstream rhythms in physiology.

In an effort to map these connections between the core clock and the diverse biological processes it regulates, researchers have devoted significant time and effort to studying transcriptional rhythms (6 ⇓ ⇓ ⇓ –10). Although extremely informative, most circadian studies of this nature have analyzed one or two organs by using microarrays, and little work has been done to analyze either clock control at the organism level or regulation of the noncoding transcriptome. To address these gaps in our knowledge, we used RNA-sequencing (RNA-seq) and DNA arrays to profile the transcriptomes of 12 different mouse organs: adrenal gland, aorta, brainstem, brown fat, cerebellum, heart, hypothalamus, kidney, liver, lung, skeletal muscle, and white fat. We sampled organs every 6 h by RNA-seq and every 2 h by arrays, to develop an atlas of mouse biological space and time.

Using this resource, we examined the genomic characteristics of the rhythmic coding and noncoding transcriptomes, the differences between organs in timing (phase) and identity of oscillating transcripts, and the functional implications of rhythmic regulation in various biological pathways. Lastly, we explored the potential medical impact of circadian genes as drug targets and disease-associated genes. It is our hope that this work provides a rich dataset to the research community that could power many future studies.


8.3 Extensions of the Laws of Inheritance

Mendel studied traits with only one mode of inheritance in pea plants. The inheritance of the traits he studied all followed the relatively simple pattern of dominant and recessive alleles for a single characteristic. There are several important modes of inheritance, discovered after Mendel’s work, that do not follow the dominant and recessive, single-gene model.

Alternatives to Dominance and Recessiveness

Mendel’s experiments with pea plants suggested that: 1) two types of “units” or alleles exist for every gene 2) alleles maintain their integrity in each generation (no blending) and 3) in the presence of the dominant allele, the recessive allele is hidden, with no contribution to the phenotype. Therefore, recessive alleles can be “carried” and not expressed by individuals. Such heterozygous individuals are sometimes referred to as “carriers.” Since then, genetic studies in other organisms have shown that much more complexity exists, but that the fundamental principles of Mendelian genetics still hold true. In the sections to follow, we consider some of the extensions of Mendelism.

Incomplete Dominance

Mendel’s results, demonstrating that traits are inherited as dominant and recessive pairs, contradicted the view at that time that offspring exhibited a blend of their parents’ traits. However, the heterozygote phenotype occasionally does appear to be intermediate between the two parents. For example, in the snapdragon, Antirrhinum majus (Figure 8.12), a cross between a homozygous parent with white flowers (C W C W ) and a homozygous parent with red flowers (C R C R ) will produce offspring with pink flowers (C R C W ). (Note that different genotypic abbreviations are used for Mendelian extensions to distinguish these patterns from simple dominance and recessiveness.) This pattern of inheritance is described as incomplete dominance , meaning that one of the alleles appears in the phenotype in the heterozygote, but not to the exclusion of the other, which can also be seen. The allele for red flowers is incompletely dominant over the allele for white flowers. However, the results of a heterozygote self-cross can still be predicted, just as with Mendelian dominant and recessive crosses. In this case, the genotypic ratio would be 1 C R C R :2 C R C W :1 C W C W , and the phenotypic ratio would be 1:2:1 for red:pink:white. The basis for the intermediate color in the heterozygote is simply that the pigment produced by the red allele (anthocyanin) is diluted in the heterozygote and therefore appears pink because of the white background of the flower petals.

Codominance

A variation on incomplete dominance is codominance , in which both alleles for the same characteristic are simultaneously expressed in the heterozygote. An example of codominance occurs in the ABO blood groups of humans. The A and B alleles are expressed in the form of A or B molecules present on the surface of red blood cells. Homozygotes (I A I A and I B I B ) express either the A or the B phenotype, and heterozygotes (I A I B ) express both phenotypes equally. The I A I B individual has blood type AB. In a self-cross between heterozygotes expressing a codominant trait, the three possible offspring genotypes are phenotypically distinct. However, the 1:2:1 genotypic ratio characteristic of a Mendelian monohybrid cross still applies (Figure 8.13).

Multiple Alleles

Mendel implied that only two alleles, one dominant and one recessive, could exist for a given gene. We now know that this is an oversimplification. Although individual humans (and all diploid organisms) can only have two alleles for a given gene, multiple alleles may exist at the population level, such that many combinations of two alleles are observed. Note that when many alleles exist for the same gene, the convention is to denote the most common phenotype or genotype in the natural population as the wild type (often abbreviated “+”). All other phenotypes or genotypes are considered variants (mutants) of this typical form, meaning they deviate from the wild type. The variant may be recessive or dominant to the wild-type allele.

An example of multiple alleles is the ABO blood-type system in humans. In this case, there are three alleles circulating in the population. The I A allele codes for A molecules on the red blood cells, the I B allele codes for B molecules on the surface of red blood cells, and the i allele codes for no molecules on the red blood cells. In this case, the I A and I B alleles are codominant with each other and are both dominant over the i allele. Although there are three alleles present in a population, each individual only gets two of the alleles from their parents. This produces the genotypes and phenotypes shown in Figure 8.14. Notice that instead of three genotypes, there are six different genotypes when there are three alleles. The number of possible phenotypes depends on the dominance relationships between the three alleles.

Evolution Connection

Multiple Alleles Confer Drug Resistance in the Malaria Parasite

Malaria is a parasitic disease in humans that is transmitted by infected female mosquitoes, including Anopheles gambiae, and is characterized by cyclic high fevers, chills, flu-like symptoms, and severe anemia. Plasmodium falciparum and P. vivax are the most common causative agents of malaria, and P. falciparum is the most deadly. When promptly and correctly treated, P. falciparum malaria has a mortality rate of 0.1 percent. However, in some parts of the world, the parasite has evolved resistance to commonly used malaria treatments, so the most effective malarial treatments can vary by geographic region.

In Southeast Asia, Africa, and South America, P. falciparum has developed resistance to the anti-malarial drugs chloroquine, mefloquine, and sulfadoxine-pyrimethamine. P. falciparum, which is haploid during the life stage in which it is infective to humans, has evolved multiple drug-resistant mutant alleles of the dhps gene. Varying degrees of sulfadoxine resistance are associated with each of these alleles. Being haploid, P. falciparum needs only one drug-resistant allele to express this trait.

In Southeast Asia, different sulfadoxine-resistant alleles of the dhps gene are localized to different geographic regions. This is a common evolutionary phenomenon that comes about because drug-resistant mutants arise in a population and interbreed with other P. falciparum isolates in close proximity. Sulfadoxine-resistant parasites cause considerable human hardship in regions in which this drug is widely used as an over-the-counter malaria remedy. As is common with pathogens that multiply to large numbers within an infection cycle, P. falciparum evolves relatively rapidly (over a decade or so) in response to the selective pressure of commonly used anti-malarial drugs. For this reason, scientists must constantly work to develop new drugs or drug combinations to combat the worldwide malaria burden. 2

Sex-Linked Traits

In humans, as well as in many other animals and some plants, the sex of the individual is determined by sex chromosomes—one pair of non-homologous chromosomes. Until now, we have only considered inheritance patterns among non-sex chromosomes, or autosomes. In addition to 22 homologous pairs of autosomes, human females have a homologous pair of X chromosomes, whereas human males have an XY chromosome pair. Although the Y chromosome contains a small region of similarity to the X chromosome so that they can pair during meiosis, the Y chromosome is much shorter and contains fewer genes. When a gene being examined is present on the X, but not the Y, chromosome, it is X-linked .

Eye color in Drosophila, the common fruit fly, was the first X-linked trait to be identified. Thomas Hunt Morgan mapped this trait to the X chromosome in 1910. Like humans, Drosophila males have an XY chromosome pair, and females are XX. In flies the wild-type eye color is red (X W ) and is dominant to white eye color (X w ) (Figure 8.15). Because of the location of the eye-color gene, reciprocal crosses do not produce the same offspring ratios. Males are said to be hemizygous , in that they have only one allele for any X-linked characteristic. Hemizygosity makes descriptions of dominance and recessiveness irrelevant for XY males. Drosophila males lack the white gene on the Y chromosome that is, their genotype can only be X W Y or X w Y. In contrast, females have two allele copies of this gene and can be X W X W , X W X w , or X w X w .

In an X-linked cross, the genotypes of F1 and F2 offspring depend on whether the recessive trait was expressed by the male or the female in the P generation. With respect to Drosophila eye color, when the P male expresses the white-eye phenotype and the female is homozygously red-eyed, all members of the F1 generation exhibit red eyes (Figure 8.16). The F1 females are heterozygous (X W X w ), and the males are all X W Y, having received their X chromosome from the homozygous dominant P female and their Y chromosome from the P male. A subsequent cross between the X W X w female and the X W Y male would produce only red-eyed females (with X W X W or X W X w genotypes) and both red- and white-eyed males (with X W Y or X w Y genotypes). Now, consider a cross between a homozygous white-eyed female and a male with red eyes. The F1 generation would exhibit only heterozygous red-eyed females (X W X w ) and only white-eyed males (X w Y). Half of the F2 females would be red-eyed (X W X w ) and half would be white-eyed (X w X w ). Similarly, half of the F2 males would be red-eyed (X W Y) and half would be white-eyed (X w Y).

Visual Connection

What ratio of offspring would result from a cross between a white-eyed male and a female that is heterozygous for red eye color?

Discoveries in fruit fly genetics can be applied to human genetics. When a female parent is homozygous for a recessive X-linked trait, she will pass the trait on to 100 percent of her male offspring, because the males will receive the Y chromosome from the male parent. In humans, the alleles for certain conditions (some color-blindness, hemophilia, and muscular dystrophy) are X-linked. Females who are heterozygous for these diseases are said to be carriers and may not exhibit any phenotypic effects. These females will pass the disease to half of their sons and will pass carrier status to half of their daughters therefore, X-linked traits appear more frequently in males than females.

In some groups of organisms with sex chromosomes, the sex with the non-homologous sex chromosomes is the female rather than the male. This is the case for all birds. In this case, sex-linked traits will be more likely to appear in the female, in whom they are hemizygous.

Concepts in Action

Watch this video to learn more about sex-linked traits.

Linked Genes Violate the Law of Independent Assortment

Although all of Mendel’s pea plant characteristics behaved according to the law of independent assortment, we now know that some allele combinations are not inherited independently of each other. Genes that are located on separate, non-homologous chromosomes will always sort independently. However, each chromosome contains hundreds or thousands of genes, organized linearly on chromosomes like beads on a string. The segregation of alleles into gametes can be influenced by linkage , in which genes that are located physically close to each other on the same chromosome are more likely to be inherited as a pair. However, because of the process of recombination, or “crossover,” it is possible for two genes on the same chromosome to behave independently, or as if they are not linked. To understand this, let us consider the biological basis of gene linkage and recombination.

Homologous chromosomes possess the same genes in the same order, though the specific alleles of the gene can be different on each of the two chromosomes. Recall that during interphase and prophase I of meiosis, homologous chromosomes first replicate and then synapse, with like genes on the homologs aligning with each other. At this stage, segments of homologous chromosomes exchange linear segments of genetic material (Figure 8.17). This process is called recombination , or crossover, and it is a common genetic process. Because the genes are aligned during recombination, the gene order is not altered. Instead, the result of recombination is that maternal and paternal alleles are combined onto the same chromosome. Across a given chromosome, several recombination events may occur, causing extensive shuffling of alleles.

When two genes are located on the same chromosome, they are considered linked, and their alleles tend to be transmitted through meiosis together. To exemplify this, imagine a dihybrid cross involving flower color and plant height in which the genes are next to each other on the chromosome. If one homologous chromosome has alleles for tall plants and red flowers, and the other chromosome has genes for short plants and yellow flowers, then when the gametes are formed, the tall and red alleles will tend to go together into a gamete and the short and yellow alleles will go into other gametes. These are called the parental genotypes because they have been inherited intact from the parents of the individual producing gametes. But unlike if the genes were on different chromosomes, there will be no gametes with tall and yellow alleles and no gametes with short and red alleles. If you create a Punnett square with these gametes, you will see that the classical Mendelian prediction of a 9:3:3:1 outcome of a dihybrid cross would not apply. As the distance between two genes increases, the probability of one or more crossovers between them increases and the genes behave more like they are on separate chromosomes. Geneticists have used the proportion of recombinant gametes (the ones not like the parents) as a measure of how far apart genes are on a chromosome. Using this information, they have constructed linkage maps of genes on chromosomes for well-studied organisms, including humans.

Mendel’s seminal publication makes no mention of linkage, and many researchers have questioned whether he encountered linkage but chose not to publish those crosses out of concern that they would invalidate his independent assortment postulate. The garden pea has seven chromosomes, and some have suggested that his choice of seven characteristics was not a coincidence. However, even if the genes he examined were not located on separate chromosomes, it is possible that he simply did not observe linkage because of the extensive shuffling effects of recombination.

Epistasis

Mendel’s studies in pea plants implied that the sum of an individual’s phenotype was controlled by genes (or as he called them, unit factors), such that every characteristic was distinctly and completely controlled by a single gene. In fact, single observable characteristics are almost always under the influence of multiple genes (each with two or more alleles) acting in unison. For example, at least eight genes contribute to eye color in humans.

Concepts in Action

Eye color in humans is determined by multiple alleles. Use the Eye Color Calculator to predict the eye color of children from parental eye color.

In some cases, several genes can contribute to aspects of a common phenotype without their gene products ever directly interacting. In the case of organ development, for instance, genes may be expressed sequentially, with each gene adding to the complexity and specificity of the organ. Genes may function in complementary or synergistic fashions, such that two or more genes expressed simultaneously affect a phenotype. An apparent example of this occurs with human skin color, which appears to involve the action of at least three (and probably more) genes. Cases in which inheritance for a characteristic like skin color or human height depend on the combined effects of numerous genes are called polygenic inheritance.

Genes may also oppose each other, with one gene suppressing the expression of another. In epistasis , the interaction between genes is antagonistic, such that one gene masks or interferes with the expression of another. “Epistasis” is a word composed of Greek roots meaning “standing upon.” The alleles that are being masked or silenced are said to be hypostatic to the epistatic alleles that are doing the masking. Often the biochemical basis of epistasis is a gene pathway in which expression of one gene is dependent on the function of a gene that precedes or follows it in the pathway.

An example of epistasis is pigmentation in mice. The wild-type coat color, agouti (AA) is dominant to solid-colored fur (aa). However, a separate gene C, when present as the recessive homozygote (cc), negates any expression of pigment from the A gene and results in an albino mouse (Figure 8.18). Therefore, the genotypes AAcc, Aacc, and aacc all produce the same albino phenotype. A cross between heterozygotes for both genes (AaCc x AaCc) would generate offspring with a phenotypic ratio of 9 agouti:3 black:4 albino (Figure 8.18). In this case, the C gene is epistatic to the A gene.


3 Main Types of Genetic Mechanisms | Genetics

The following points highlight the three main types of genetic mechanisms. The types are: 1. Immuno-Genetics 2. The HLA System 3. The Rh Factor.

Type # 1. Immuno-Genetics:

Genetic mechanisms which control immune responses have opened up an entire new field of immuno-genetics. Basically it is the study of antigens, antibodies and their reactions. An antigen is a substance present in the body or introduced from outside which can initiate an immune reaction.

The antigens present on the surface of red and white blood cells are important in immuno-genetics. The immune reactions in response to the antigen take place in the lymphoid organs (spleen, lymph nodes and tonsils) and result in the production of antibodies or sensitized lymphocytes which are effective in eliminating the antigen from the body. As there are millions of potential antigens, there are many millions of species of antibody molecules that are synthesised by the immune system.

Antibodies are serum proteins belonging to the group immunoglobulins (Ig). Each antibody is made up of two kinds of protein chains designated light and heavy (L and H) chains.

The heavy chains are of 5 types:

There are thus five classes of immunoglobulins named according to the type of heavy chain present, that is IgG, IgA, IgM, IgD and IgE of these IgG is most abundant in the serum.

The structure and properties of the different immunoglobulins are genetically controlled. Basically IgG is made up of two light (L) and two heavy (H) chains linked by disulphide bonds. The L chains have 214 and H chains 440 amino acids. Each of the light and heavy chains consists of a constant (C) half and a variable (V) half (Fig. 21.8).

The ability of an organism to produce an enormous number of antibodies lies in the amino acid sequences of the V regions of the light and heavy chains. Thus there are a large number of immunoglobulin chains in which the V region is different but the C region is the same.

The antigen binds to the antibody in the V regions of the light and heavy chains the combining site determines the specificity for the antigen. The antibody molecule appears V-shaped in the electron microscope. The two antigen-binding sites containing identical amino acid sequences are located at the ends of the two arms. Thus two antigens of the same type can link to a single antibody molecule.

Two questions have been raised, firstly, what genetic mechanisms are responsible for the immense variability of the V region? Secondly are genes coding for the immunoglobulin chains present in the gamete or are produced during somatic differentiation? Proponents of the germ line theory believe that all the immunoglobulin genes are transmitted through the gametes.

There would thus be many different V genes and a large number of copies of one or a few C genes. According to the somatic differentiation theory the variety of V genes is created during lymphocyte differentiation by somatic mutation or by somatic recombination.

The current views combine both the above theories and envision many V genes containing coding sequences and spacers in the germ cells, and a small number of C genes. The innumerable variants of the V genes arise during somatic recombination in the cells of the immune system called B lymphocytes.

There are two types of light chains in the mouse as well as human beings, one called kappa the other lambda, each with a characteristic amino acid sequence. In mouse the variable regions of both kappa and lambda chains are coded by a large number of V genes which have been identified in the DNA of embryonal cells.

There may be several hundred V genes, each gene consisting of two coding regions separated by a silent spacer. The first coding segment is translated into a leader sequence about 20 amino acids long and is thought to be involved in the movement of the antibody across the cell membrane. It is eventually cut off before the antibody molecule is transported.

The second coding region is specific for about 95 amino acids out of the 108 constituting the V region. The remaining 13 amino acids, of the V region are specified by a J gene situated much downstream, that is toward the 3′ end near the gene for the C region.

There is a long non- coded spacer between the V and J genes. When the light chains are of the lambda type in mouse, there are 4 genes for the C region each having its own J gene. The V and C sequences join at the J region to produce the immunoglobulin gene.

Type # 2. The HLA System:

The genetic mechanisms controlling transplantation antigens play a significant role in the organ transplant technique. The treatment of certain human diseases requires transfer of grafts from a host to a recipient individual of a different genetic make-up (allograft). The existence of transplantation antigens first became known from skin grafting experiments in mice.

Whether a graft would be rejected or accepted by the recipient mouse depended upon the presence of histocompatibility antigens present on the skin and other tissue cells. From the results of genetic experiments it was concluded that the histocompatibility antigens were controlled by several different genes, each gene having multiple alleles.

That the red blood cells in humans contain blood group antigens on their surface. These antigens are important in blood transfusions. The white blood cells also carry several antigens which are important in organ transplantation.

These are called histocompatibility antigens and are found to be controlled by four gene loci A, B, C and D on chromosome 6. The histocompatibility (histo meaning tissue) antigens and their corresponding genes constitute the HLA (human leukocyte antigen) system.

When a graft is transplanted, the lymph nodes of the recipient individual respond to the histocompatibility antigens of the genetically different tissue by producing lymphocytes which are of two types, the T lymphocytes (thymus dependent) and the B lymphocytes (cells equivalent to the bursa in birds).

The T cells are important in graft rejection, and are involved in the cell mediated immune response (CMI). The B cells are involved in the humoral responses (HR) which produce antibodies against viruses, bacteria and such invasions, as well as against graft cells of the host. It is mainly the T cells which respond to the histocompatibility antigens present on the grafted tissue.

The genetics of HLA has been studied by performing breeding experiments in mice. When two mice homozygous for the histocompatibility antigens are crossed, the F1 mice are able to accept grafts from both parents. When F1 mice are inbred, three of the progeny mice accept grafts from either parent, while one mouse shows rejection.

Applying the principles of Mendelian inheritance one can conclude that the parental mice differ at a single gene locus. From similar experiments a number of loci controlling histocompatibility antigens could be determined. Each locus has several alleles. One complex locus H-Z controls the strong transplantation antigens in mouse.

In humans, the strongest transplantation antigens are controlled by four distinct loci A, B, C and D on chromosome 6 (Fig. 21.9). Additional genes related to histocompatibility also lie in the adjacent regions.

Studies on different individuals in the population have revealed that the A gene has more than 12 alleles, and B gene at least 20 alleles controlling more than 32 histocompatibility antigens. As the A and B genes are only one map unit apart, there is very little chance of crossing over between them they are thus transmitted together in most cases.

Since any allele at A can be associated with any allele at B, the number of possible combinations of the alleles of A and B genes in the population is about 240 (12 x 20). A combination of the alleles of the A and B genes is called the haplotype. Designating the alleles of the A locus as A1, A2, …, A12, and at B as B1, B2,…, B20, suppose one chromosome 6 of a particular individual is carrying the alleles A5 and B9.

The haplotype in this case would be written as 5 9 (A allele is written to the left and B allele to the right). As there are two number 6 chromosomes in a cell, the HLA genotype of a person consists of two haplotypes.

The presence of a particular allele in the individual is determined serologically from the existence of a specific antigen on the leukocyte surface by the technique of leukocyte typing, also called HLA typing. Thus individuals may be homozygous or heterozygous for any pair of alleles.

Due to the highly polymorphic and complex nature of the HLA locus, it is very unlikely that any two persons picked at random should have the same set of leukocyte antigens. These genetic differences lead to rejection of allografts in organ transplantation. Due to this reason the host and recipient HLA genotypes have to be closely matched.

Some Other Loci Linked to HLA:

The gene which is supposed to control the quantity and quality of the immune responses (IR gene) is said to be closely linked to the HLA genes. Some of the immunological disorders are also associated with HLA, such as psoriasis with alleles B8 and B15 of HLA ankylosing spondylitis with B13 and B7 diabetes mellitus with an allele of the D gene and multiple sclerosis with alleles of the A, B and D genes.

Type # 3. The Rh Factor:

In 1940, Wiener and Landsteiner discovered that an antigenic factor Rh, which is found on the surface of red blood cells of the Indian brown monkey (Macacus rhesus), is also present in man. They injected the blood of rhesus monkey into rabbits and guinea pigs. Antibodies produced in the blood serum of these animals were found to agglutinate the red cells of the rhesus monkey.

When Landsteiner and Wiener added the same antiserum to human blood, they found to their surprise that the red cells of about 85% of the persons tested were also agglutinated. It was thus revealed that human blood contained the same Rh antigen that was found in the rhesus monkey.

In the same year, Wiener and Peters showed a similarity between the specificity of the animal antibody and an antibody found in the serum of some patients who had shown transfusion reactions. The animal and the human antibodies could both react with the same red cells. The name Rh (after rhesus) was given to the antigen and anti-Rh to the antibody.

Later studies on family pedigrees showed that Rh antigens in humans are controlled by an autosomal dominant gene D. Persons having one or both dominant alleles (DD or Dd) carry Rh or D antigens on their red cells and are said to be Rh positive (Rh + ). Persons having two recessive alleles (dd) of the gene lack Rh antigen and are said to be Rh negative (Rh – ). There are more than 30,000 Rh or D sites on the surface of each red cell.

As in the case of the ABO blood groups, Rh is also important in blood transfusions. If the blood of an Rh positive person is transfused into an Rh negative person, it will elicit the formation of anti-Rh antibodies in the Rh – recipient. These antibodies will agglutinate the red blood cells of the transfused blood as they carry the Rh antigen on their surface.

The first transfusion of Rh + blood into an Rh – individual is without severe reaction. But in a subsequent transfusion with Rh + blood, the sensitized individual will produce increased amounts of antibodies against the Rh antigen in the transfused blood, resulting in severe reaction or even death. It should be noted however, that there are no natural anti-Rh antibodies in the blood of an Rh + or Rh – individual. Therefore, an Rh – person can donate blood to an Rh + individual without bad consequences.

Immediately after the discovery of Rh factor, an association was traced between Rh and haemolytic diseases of the newborn (erythroblastosis fetalis) by Levine (1942). These are conditions where newborn infants suffer from anaemia, jaundice, enlarged spleen or liver, in severe cases stillbirth or death soon after birth. This is due to Rh incompatibility between the mother and fetus.

When the mother is Rh negative and carrying two recessive alleles dd of the Rh gene D, and the father is Rh positive, either homozygous DD or heterozygous Dd, then according to Mendelian inheritance the genotype of the foetus could be any one of the following:

If the foetus is dd (Rh – ) the pregnancy is normal. Only the Rh + foetus with Dd genotype creates problems at birth. The gene for Rh (D gene) is transmitted from the father to the foetus (when mother is Rh – ).

If the father is homozygous for the D gene (DD), then all the conceptions will produce Rh positive foetuses if the father is heterozygous (Dd), then there is 50% chance at each conception that the foetus would be Rh + . In addition to the D antigen which distinguishes Rh positive and Rh negative persons, there are other antigens in the Rh system, the main ones being C, E, c and e.

As explained in the case of blood transfusions from Rh + to Rh – persons, the first pregnancy with an Rh + foetus may develop low levels of antibody in the mother and remain free of complications. It is also possible for subsequent pregnancies with Rh + foetus to be normal. This is so because the circulatory systems of the foetus and mother are separate, eliminating any chance for the foetal Rh + antigen to reach the mother’s blood.

However, problems do arise in second or later pregnancies due to some defect or breakage in the capillaries of the placenta which allows foetal blood to leak into the maternal circulation. This usually happens about the time of birth. In such cases the Rh + blood of the foetus produces antibodies in the mother’s blood, which may pass back across the placenta into the foetus.

The antibodies react with foetal red cells and cause haemolysis. The reaction may be mild in the first pregnancy with low levels of antibody in the mother’s blood. In subsequent pregnancies in the sensitized woman, another exposure to the Rh + antigen triggers an immediate response producing high levels of antibody in the blood (Fig. 21.10).

It is possible to treat the woman for prevention of Rh-caused disease in future births. Within 72 hours of the birth of every Rh + infant, the Rh – mother is given an intramuscular dose of the anti-Rh antibody (Anti-D gamma-globulin), commercially available as RhoGAM.

This antibody destroys the foetal red cells that have entered the mother’s circulation so that they (foetal cells) cannot stimulate the production of anti-D antibodies in the mother. The process is called passive immunisation.

The Genetic Mechanism of Rh:

Rh factor actually comprises a complex group of related antigens known as the Rh system. The genetic mechanisms controlling the Rh system remain confusing. Two genetic models have been proposed, one by Fisher and Race, the other by Wiener. In the Fisher-Race Model, inheritance of Rh is controlled by 3 closely linked genes, designated C, D and E which are present on an autosomal chromosome.

There are two alleles of each gene: C and c, D and d, E and e. An individual could be homozygous or heterozygous for any of the 3 genes. It should be noted that the D gene produces the D antigen, but the allele d does not produce any antigen (silent gene or amorph). All the other alleles C, c, E and e produce their respective antigens.

In the Fisher-Race system, the gene as well as the antigen it produces on the red cell are given the same symbol. If one chromosome of an individual carried the alleles DCe, and the homologous chromosome had DcE at identical loci, the antigens present on the person’s RBCs would be D, C, c, E and e. Each of the antigens can be detected by testing the RBCs with antisera specific for the various antigens.

A somewhat different model has been proposed by Wiener. According to Wiener there is a single gene with multiple alleles (8 major alleles) controlling Rh. The 8 alleles are R°, R 1 ,R 2 ,R z , r, r 1 , r” r y . Each gene produces an antigen on the red cell called an agglutinogen. Each agglutinogen can be recognised by reaction with specific antibodies.

Both the models of Fisher-Race and Wiener seem to arrive at the same conclusion. The 3 genes of Fisher-Race can produce 8 different combinations: CDE, CDe, CdE, cDE, cdE, Cde, cDe, cde. The combinations of the alleles of the 3 genes in a way correspond to the 8 alleles of Wiener. Most geneticists use the Fisher-Race system as it is more convenient.


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