General Genetics Ayesha M. Khan Spring 2013

Sex Determination in Drosophila The fruit fly Drosophila melanogaster, has eight chromosomes: three pairs of autosomes and one pair of sex chromosomes Presence of the Y chromosome does not determine maleness in Drosophila Each fly’s sex is determined by a balance between genes on the autosomes and genes on the X chromosome. This type of sex determination is called the genic balance system. The X chromosome contains genes with female producing effects, whereas the autosomes contain genes with male-producing effects. Fly’s sex is determined by the X:A ratio, the number of X chromosomes divided by the number of haploid sets of autosomal chromosomes.

Sex Determination in Drosophila An X:A ratio of 1.0 produces a female fly; an X:A ratio of 0.5 produces a male. X:A ratio less than 0.5: a male phenotype is produced, but the fly is weak and sterile—metamales. X:A ratio between 1.0 and 0.50: intersex fly, with a mixture of male and female characteristics. X:A ratio > than 1.0 : Female phenotype is produced, but these flies (called metafemales) have serious developmental problems and many never emerge from the pupal case.

Chromosome complements and sexual phenotypes in Drosophila

Sex Determination in Humans XX-XY sex determination Presence of a gene on the Y chromosome determines maleness

Turner syndrome: XO; 1/3000 female births Immature secondary sex characteristics Normal intelligence Sterile Klinefelter syndrome: XXY, or XXXY, or XXXXY, or XXYY; 1/1000 male births Most have normal intelligence Poly-X females: 1/1000 female births Normally regular secondary sex characteristics Fertile Mental retardation slightly higher There are no known cases in which a person is missing both X chromosomes, an indication that at least one X chromosome is necessary for human development. Presumably, embryos missing both Xs are spontaneously aborted in the early stages of development.

The role of sex chromosomes The X chromosome contains genetic information essential for both sexes; at least one copy of an X chromosome is required for human development. The male-determining gene is located on the Y chromosome. A single copy of this chromosome, even in the presence of several X chromosomes, produces a male phenotype.

The role of sex chromosomes (contd) The absence of the Y chromosome results in a female phenotype. Genes affecting fertility are located on the X and Y chromosomes. A female usually needs at least two copies of the X chromosome to be fertile. Additional copies of the X chromosome may upset normal development in both males and females, producing physical and mental problems that increase as the number of extra X chromosomes increases.

The male-determining gene in humans David Page (1987) Analyzed the chromosomes of sex-reversed XX men, rare individuals who look like men but have two X chromosomes instead of one X chromosome and one Y chromosome. Page discovered that sex-reversed males carried genes from a 140-kilobase region on the short arm of the Y chromosome. Presumably, this region had been transferred to the X chromosome during a translocation. Subsequent experiments narrowed down this region and found that one gene, the sex-determining region of the Y, or SRY was the master regulator of sex determination. The presence of just this region from the Y chromosome is thus sufficient to cause male development . Although SRY is the primary determinant of maleness in humans, other genes (some X linked, others Y linked, and still others autosomal) also play a role in fertility and the development of sex differences.

The SRY Gene How the Y chromosome determines sex: The SRY gene, located on the Y chromosome, is the primary determinant of sexual development. That is, if a developing embryo has a functional SRY gene in its cells, it will develop as a male. And, if there is no functional SRY, the embryo develops as female. Although the SRY gene is usually on the Y chromosome, it occasionally gets transferred to the X. this leads to 46,XX males Also, sometimes the SRY gene is inactivated by mutation. Leading to 46,XY females (Swyer syndrome) it is also possible to have a partially inactive SRY gene

Androgen-insensitivity syndrome -Females; X and Y chromosome -Caused by the defective androgen receptor; cells are insensitive to testosterone, and female characteristics develop. -The gene for the androgen receptor is located on the X chromosome; so persons with this condition always inherit it from their mothers. In a human embryo with a Y chromosome, the SRY gene causes the gonads to develop into testes, which produce testosterone. Testosterone stimulates embryonic tissues to develop male characteristics. But, for testosterone to have its effects, it must bind to an androgen receptor. This receptor is defective in females with androgen-insensitivity syndrome; consequently, their cells are insensitive to testosterone, and female characteristics develop.

Sex-linked characteristics Sex-Linked Characteristics Are Determined by Genes on the Sex Chromosomes Genes on the X chromosome determine X-linked characteristics; those on the Y chromosome determine Y-linked characteristics.

Thomas Morgan (1866-1945) The first person to explain sex-linked inheritance was the American biologist Thomas Hunt Morgan X-Linked White Eyes in Drosophila In both humans and fruit flies (Drosophila melanogaster) females have two X chromosomes, while males have X and Y

Sex Linkage Morgan (1910) found a mutant white-eyed male fly, and used it in a series of experiments that showed a gene for eye color located on the X chromosome. a. First, he crossed the white-eyed male with a wild-type (red-eyed) female. All F1 flies had red eyes. Therefore, the white-eyed trait is recessive. b. Next, F1 were interbred. They produced an F2 with: i. 3,470 red-eyed flies. ii. 782 white-eyed flies. All of the F2 white-eyed flies were male. In fact, Morgan found three white-eyed males among the 1237 progeny, but he assumed that the white eyes were due to new mutations.

X-linked inheritance of white eyes in Drosophila: Red-eyed female  white-eyed male

X-linked inheritance of white eyes in Drosophila: The F1 flies are interbred to produce the F2 =>This finding was clearly not the expected result for a simple recessive trait, which should appear in ¼ of both male and female F2 offspring.

What happened when white eyed males and red eyed females from second generation were crossed? =>Equal number of offspring with each eye color

Morgan’s hypothesis was that this eye color gene is located on the X chromosome. Males therefore cannot be either homozygous or heterozygous but are said to be hemizygous for X-linked loci. -Females may be homozygous or heterozygous. The wild-type female in the original cross was w+/w+ (homozygous for red eyes). -Females only show the white eyes trait if they inherit mutant genes on both X chromosomes. “Sex-linked inheritance”

Reciprocal cross: Homozygous white-eyed female  red-eyed ( wild-type) male

Reciprocal cross: The F1 flies are interbred to produce the F2

Morgan’s discovery of X-linked inheritance showed that when results of reciprocal crosses are different, and ratios differ between progeny of different sexes, the gene involved is likely to be X-linked (sex-linked). This was strong evidence that genes are located on chromosomes. Morgan received the 1933 Nobel Prize for Physiology or Medicine for this work.

Non-Disjunction of X Chromosomes 1. Morgan’s work showed that crossing a white-eyed female (w/w) with a red-eyed male (w+/Y) produces an F1 of white-eyed males (w/Y) and red-eyed females (w+/w). His student, Bridges, found that about 1 in 2,000 of the offspring was an exception, either a white-eyed female or red-eyed male. 2. Bridges’ hypothesis was that chromatids failed to separate normally during anaphase of meiosis I or II, resulting in non- disjunction. 3. Non-disjunction can involve either autosomes or sex chromosomes. For the eye-color trait, X chromosome non- disjunction was the relevant event. Non-disjunction in an individual with a normal set of chromosomes is called primary non-disjunction.

Nondisjunction in meiosis involving the X chromosome