Genetics Lecture 13, 9/29: Primary Sexual determination, Genetic diseases, dosage compensation

• • Human Embryonic, sexual differentiation (primary)
• o A relatively early process.
• o By the 5th week of gestation developmental gonads have appeared. Initially associated with the kidney.
• • Outer cortex
• Can become an ovary
• • Inner mendula
• Has the ability to develop into testes.
• o Ducts
• • Male → wolffian ducts
• • Female → mullarian ducts
• • The SRY has the testes determining factor. If this is present the development of the testes and male ducts is triggered. If it is NOT present (no Y chromosome) by week 12 we start to produce oogonia. Then we begin meiosis and by the end of the 25th week meiosis I is complete and all of the potential eggs are present in the female.
  
• • What can go wrong with sex chromosomes. (7:25)
• o Non-disjunction event: during meiosis, the sex chromosome pair fails to separate so you get unequal distribution of sex chromosomes in the gametes.
• o This leads to a number of syndromes associated with unusual sex chromosome arrangements.
• o Kleinfelter syndrome: males with two X chromosomes and a Y chromosome. These individuals are labeled 47 XXY where 47 is the number of chromosomes and XXY is the arrangement of the sex chromosomes.
• • Individuals can also have other arrangements: 48 XXXY, 48 IIYY, 49 XXXXY, 49 XXXYY
• • Generally the greater the number of X chromosomes the worse the syndrome.
• • Normal male ducts and normal genitals but the testes fail to form properly. The result is sterility.
• • Unusually long arms and legs, large hands and feet, undergo some female secondary sexual development including rounding of hips and some breast growth, below avg. intelligence.
• o Turner syndrome (14:40)
• • Also known as “45X”. Missing an X chromosome.
• • Female with normal female genitalia, normal female ducts, incomplete ovaries → sterility
• • Short in stature, skin flap on back of their necks
• o 47 XXX syndrome
• • some have it and are normal
• • others are underdeveloped sex characteristics, below avg. intelligence and sterile
• • ALSO: 48 XXXX and 49 XXXXX → traits become more pronounced.
• o 47 XYY syndrome (20:00)
• • Male, above average height. Below avg. intelligence, and socially awkward.
• • Theorized that this is more common in a prison population then the population at whole (controversial).
• • Ratio of males to females (not always one:one)
• o in theory, a heteromorphic (male) individual should make equal number of X and Y gamets.
• o Look at two ratios of males to females in the population
• o (25:25) Primary sex ratio: Ratio of male to female conceptions
• o Secondary Sex ratio: male to female births
• o Secondary sex ratios:
• • Caucasians: 1.06 (106 males to 100 females)
• o Question: Does the primary sex ratio 1.6 mean that more females die in the embryonic period than males?
• • observe miscarriages and abortion
• • primary sex ratio can be anywhere from 1.08 to 1.6 → this suggests that there are more male conceptions than female.
• o Primary sex ratio of 1 assumes:
• • Male will produce same number of x and y gamets
• • Each gamete type has the same viability in the reproductive tract
• • The egg is equally receptive to both gamete types.
• o (32:45) Current theory as to why “more males are born than females” is that the gamete bearing the Y chromosome is lighter and therefore faster than the gamete with an X chromosome.
• • Dosage compensation (35:30)
• o All of the autosomal chromosomes come in pairs.
• o Sex chromosomes – females have 2 X chromosomes males have 1 X chromosome. Twice as many copies of the X chromosome genes in females
• o Problematic – need to balance the amount of genes in all sexes.
• o Barr and Bertman – looking at DNA in interphase and they identified a dark staining body in the nucleus of females. They called it a Barr body. In females, one of the two X chromosomes is inactivated.
• o Barr body: inactivated X chromosome
• o How is the inactivation of one X chromosome determined?
• • Lyon hypothesis – the inactivation of the X chromosome is random. The same x chromosome is inactivated in every cell of an individual
• o Work to support lyon looks at:
• • Glucose – 6 – phosphate dehydrogenase (X chromosome gene)
• • Looked at a large number of individuals that were heterozygotes for the gene.
• • If the lyon hypothesis is correct then 50% of these will have the wildtype copy of the gene and 50% will have the mutant. (they did the test and it is correct – accepted as true)
• o How do you make a Barr Body and thus inactivate the X chromosome? (46:50)
• • A region on the X chromosome is responsible for this called the X inactivation center.
• • X inactivation center contains 4 genes: one of these genes when activated produces a functional RNA. It is Believed that this RNA covers the X chromosome that is inactivated. The coating is what prevents the X chromosome from functioning.