Introductory Genetics Lecture 5 PDF

BIO207H5S Introductory Genetics Winter 2024 Lecture 5 Preeti Karwal, Ph.D. Topics covered: 1. Sex determination 2. Sex-linked inheritance XX-XY System In humans and all other placental mammals, females inherit an X chromosome from each parent, whereas males always inherit their X chromosome fr...

BIO207H5S Introductory Genetics Winter 2024 Lecture 5 Preeti Karwal, Ph.D. Topics covered: 1. Sex determination 2. Sex-linked inheritance XX-XY System In humans and all other placental mammals, females inherit an X chromosome from each parent, whereas males always inherit their X chromosome from their mother and their Y chromosome from their father. Consequently, all of the somatic cells in human females contain two X chromosomes, and all of the somatic cells in human males (also called hemizygous) contain one X and one Y chromosome. Males (heterogametic sex) produce X and Y gametes, and females (homogametic sex) produce only X gametes. In this system, referred to as the XX-XY system, the maleness is determined by sperm cells that carry the Y chromosome. Y chromosome has ~75 genes compared to 900–1400 genes on the X. Presence of Y chromosome determines maleness During early development, every human embryo is potentially hermaphroditic for the first few weeks of gestation. By the fifth week of gestation, gonadal tissues arise as a pair of gonadal (genital) ridges associated with each embryonic kidney. At this stage, its gonadal phenotype is sexually indifferent or neutral, so the male or female reproductive structures cannot be distinguished. The cortex of this neutral gonadal tissue is capable of developing into an ovary, while the medulla may develop into a testis. In addition, two sets of undifferentiated ducts called the Wolffian and Müllerian ducts exist in each embryo. Wolffian ducts differentiate into other organs of the male reproductive tract, while Müllerian ducts differentiate into structures of the female reproductive tract. If cells of the gonads have an XY constitution, the development of the medulla into a testis is initiated around the seventh week. However, in the absence of the Y chromosome, no male development occurs, the cortex of the gonadal tissue subsequently forms ovarian tissue. Testis determining factor, a transcription factor causes the undifferentiated gonadal tissue of the embryo to form testes. Pseudoautosomal Inheritance Present on both ends of the X and Y chromosome are so-called pseudoautosomal regions (PARs) that share homology and synapse and recombine with each other during meiosis. The presence of such a pairing region is critical to segregation of the X and Y chromosomes during male gametogenesis. The remainder of the chromosome, about 95 percent of it, does not synapse or recombine with the X chromosome. Since this region is located on sex chromosomes but has two copies in both males and females like autosomal regions, it is called pseudoautosomal region. One of the X chromosomes undergoes inactivation in the somatic cells of females for dosage compensation (explained on next slide) but the PARs lying on X chromosome escape this inactivation and continue to be expressed even from the Barr body. Less or more than two copies of PARs result in genetic consequences in case of sex chromosome aneuploidies like Turner’s Syndrome (XO) – one copy of PAR and Klinefelter’s Syndrome (XXY) – three copies of PAR, respectively. Dosage Compensation Murray Barr and Ewart Bertram demonstrated a genetic mechanism in mammals that compensates for X chromosome dosage disparities. They observed a darkly staining body in the interphase cells of female cats that was absent in similar cells of males. In humans, this body can be easily demonstrated in all somatic female cells e.g., those derived from the buccal mucosa (cheek cells) or in fibroblasts (undifferentiated connective tissue cells), but not in similar male cells. This highly condensed structure called Barr body or Sex chromatin lies against the nuclear membrane and is comprised of heterochromatic inactivated X chromosome. By inactivating one of the two X chromosomes in the cells of females, the dosage of genetic information that can be expressed in males and females becomes equivalent. Single active principle: Regardless of how many X chromosomes a somatic cell possesses, all but one of them appear to be inactivated and can be seen as Barr bodies. Therefore, the number of Barr bodies follows an N - 1 rule, where N is the total number of X chromosomes present. Female Male Lyon Hypothesis Lyon postulated that the inactivation of X chromosomes occurs randomly in somatic cells at a point early in embryonic development, most likely sometime during the blastocyst 4- to 8-cell stage of development. Once inactivation has occurred, all descendant cells have the same X chromosome inactivated as their initial progenitor cell. This explanation, which has come to be called the Lyon hypothesis, was based on observations of mosaic patterns that occur in the black and yellow-orange patches of female tortoise shell and calico cats. Such X-linked coat color patterns do not occur in male cats because all their cells contain the single maternal X chromosome and are therefore hemizygous for only one X-linked coat-color allele. Female calico cat In this figure, XO confers orange colour Xo confers black colour https://www.bio.miami.edu/dana/dox/calico.html In this figure, XB confers orange colour Xb confers black colour https://www.khanacademy.org/science/biology/classical-genetics/sexlinkage-non-nuclear-chromosomal-mutations/a/x-inactivation Mechanism of Dosage Compensation A region of the mammalian X chromosome located in the p arm in humans, is called the X-inactivation center (Xic), and its genetic expression occurs only on the X chromosome that is inactivated. One of these, X-inactive specific transcript (Xist), is known to be a critical gene for X-inactivation. A long non-coding RNA that is transcribed from the XIST gene spreads over and coats the X chromosome bearing the gene that produced it. https://link.springer.com/article/10.1007/s00439-011-1027-4 XX-XO System In XX-XO system found in crickets, grasshoppers, and some other insects, sperm cells that lack an X chromosome (referred to as O) determine maleness. Females carry two X chromosomes (XX) and only produce gametes with X chromosomes – Homogametic sex X X XX Males carry only one X chromosome (XO) and produce some gametes with X chromosomes and some gametes with no sex chromosomes at all – Heterogametic sex X O XO ZZ-ZW System In the ZZ-ZW sex determination system found in birds, snakes, some amphibians, fish and insects, females carry the mismatched chromosome pair (ZW) and males carry the identical pair (ZZ). Females produce gametes with Z chromosome or with W chromosome – Heterogametic sex Males carry two X chromosomes (ZZ) and only produce gametes with Z chromosomes – Homogametic sex Haplodiploidy It is found in insects in the order Hymenoptera including bees, ants and wasps. Sex is based on the number of chromosomes found per cell. There are no sex chromosomes. Males develop from unfertilized eggs – Haploid Females develop from fertilized eggs - Diploid TABLE 4.1 Some common sex-determining systems System Mechanism XX-XO Females XX XX-XY Females XX Heterogametic Sex Organisms Males X Male Some grasshoppers and other insects Males XY Male Many insects, fishes, amphibians, reptiles; mammals, including humans Table 4.1 Some common sexdetermining Males ZZsystems Female ZZ-ZW Females ZW Butterflies, birds; some reptiles and amphibians Genic sex determination No distinct sex chromosomes Sex determined by genes on undifferentiated chromosomes Varies Some plants, fungi, protozoans, and fishes Environmental sex determination Sex determined by environmental factors None Some invertebrates, turtles, alligators Sex determination in Drosophila melanogaster Y chromosome is not involved in sex determination in Drosophila melanogaster. Instead, Bridges proposed that the X chromosomes and autosomes together play a critical role in sex determination. The Chromosomes of Drosophila melanogaster The diploid chromosome complements of a male and a female Drosophila melanogaster. Sex-linkage One of the first cases of sex-linkage was documented by Thomas H. Morgan around 1920 during his studies of the white mutation in the eyes of Drosophila. Morgan got curious after observing a white eyed male fly in contrast to red eyed flies in his Drosophila lab cultures. The normal wildtype red eye color is dominant to white. Drawings (A) of a male and a female fruit fly, Drosophila melanogaster. The photographs (B) show the eyes of a wildtype red-eyed male and a mutant white-eyed male. Illustrations © Carolina Biological Supply Company. Used with permission. Photographs courtesy of E. R. Lozovsky. F1 : Red eyed female : Red eyed male :: 1:1 F2 : Red eyed female : Red eyed male : white eyed male :: 2:1:1 F1: Red eyed female : White eyed male :: 1:1 F2: Red eyed female : Red eyed male : white eyed male : white eyed female : 1:1:1:1 Morgan’s Hypothesis: White eye gene is a X-linked characteristic. Morgan was able to correlate these observations with the differences found in the sex-chromosome composition between male and female Drosophila. He hypothesized that the recessive allele for white eyes is found on the X chromosome, but its corresponding locus is absent from the Y chromosome. Females thus have two available gene sites, one on each X chromosome, whereas males have only one available gene site on their single X chromosome. One result of X-linkage is the crisscross pattern of inheritance, whereby phenotypic traits controlled by recessive X-linked genes are passed from homozygous mothers to all sons. Reciprocal Cross The definitive method to test for sex-linkage is conducting reciprocal crosses. Reciprocal crosses - It means to cross a male and a female that have different phenotypes, and then conduct a second set of crosses, in which the phenotypes are reversed relative to the sex of the parents in the first cross. e.g., a female of a certain genotype A is first crossed with a male of genotype B. Then, in the reciprocal cross, a female of genotype B is crossed with a male of genotype A. If the gene or trait is autosomal, it will not matter which parent has which phenotype; all of the offspring will show the dominant phenotype for F1 for any monohybrid cross. P1 Tall X P2 Dwarf F1 All Tall P1 Tall X P2 Dwarf F1 All Tall If the gene or trait is sex-linked, the offspring in F1 or F2 obtained in a reciprocal cross will be different. P1 Red eyed X P2 White eyed F1 All red eyed P1 X P2 White eyed Red eyed F1 Red eyed : White eyed 1 : 1 Non-disjunction as a proof for Chromosomal theory of inheritance Flies with unexpected phenotypes continued to appear in Morgan’s crosses at a frequency more than the expected mutation rate. Red eyed males X White eyed females F1 results: 95% - red eyed females and white eyed males (expected) 2.5% of male offspring were red eyed (unexpected) 2.5% of female offspring were white eyed (unexpected) Calvin Bridges, one of Morgan’s students investigated the genetic basis of these exceptions. He hypothesized that these white eyed females and red eyed males result from non-disjunction of chromosomes during gamete formation. To confirm this hypothesis, Bridges observed these flies with unusual phenotypes cytogenetically (under microscope) and indeed found that the appearance of rare phenotypes is associated with particular chromosomes. Therefore, this observation gave definite proof for chromosomal theory of inheritance.