SB 5: Ch 4.1, 4.3 - 4.4 Sex Chromosomes & Linkage

Sex Determination in Humans

• Determined by the presence or absence of the Y chromosome — NOT by the number of X chromosomes

• Any person carrying a Y chromosome develops male characteristics.

Evidence of sex determination from Aneuploidies

• Refers to abnormal chromosomes numbers

• Klinefelter syndrome (XXY):

  • These individuals are male (tall, thin, sterile, sometimes cognitive disabilities)

  • Significance: Shows that two X chromosomes are not enough to produce female development if a Y is present

• Turner syndrome (XO):

  • No second sex chromosome

  • These individuals are female (usually sterile, lack secondary sexual characteristics, short stature, webbed neck)

  • Significance: Shows that having only one X still produces female development — it's the absence of Y that matters, not the number of X's

SRY Gene

• Not the entire Y chromosome, but a single Y-specific gene called SRY (Sex-determining Region of Y) is the primary determinant of maleness

Evidence of SRY Gene from Sex Reversal

• Sex Reversal (XX males and XY females)

• XX Males: One X carries (any various) translocated piece of the Y that always includes a functional SRY gene

• XY Females: The Y chromosome is missing the SRY-containing region (replaced by X material), or carries a nonfunctional/mutant copy of SRY

How does SRY trigger maleness?

• With SRY (XY embryo): SRY protein activates testes development → embryonic testes secrete hormones that:

  1. Trigger development of male sex organs

  2. Prevent formation of female sex organs

• Without SRY: Ovaries develop instead of testes, and other female sex organs develop by default

Male-specific region of Y has genes that also exist on the X chromosome (like PARs)

• MSY contains SRY and genes (Y-linked copies) unrelated to sex, many of which are essential for SPERMATOGENESIS as the X-linked gene copies on the X chromosome do not supply enough protein

• Two ends of the Y chromosome are the pseudo autosomal regions (PARs) because identical DNA sequences are also on the ends of the X chromosome

• The PARs allow the dissimilar X and Y chromosomes to pair with each other during Meiosis 1 (to make XY)

Transgenic Mice Experiment to Prove SRY is the Maleness Factor

• Method — Pronuclear Injection:

  1. Isolate the DNA of the mouse SRY gene using cloning technology

  2. Create transgenic mice carrying SRY on one of their autosomes (not the sex chromosomes) — this is key, since it isolates SRY's effect from the rest of the Y chromosome

  3. Collect fertilized mouse eggs from mated females

  4. Inject the pronucleus (the sperm or egg nucleus, called a pronucleus while still in the zygote stage) with hundreds of copies of SRY gene DNA

  5. Enzymes inside the pronucleus integrate the DNA into random locations in the mouse's chromosomes

• XX mice carrying the autosomal SRY transgene developed as males, confirming SRY is the maleness-determining factor

Species vary in mechanisms of sex determination, example: fruit flies

• Females = XX, Males = XY

• Sex determined by the number of X chromosomes — Y presence/absence is irrelevant to sex determination\

• Major differences:

  • XXY: flies = female (2 X's rule); humans = male (Y present rules)

  • XO: flies = male (1 X rule); humans = female (no Y rule)

Single sex chromosome systems

• Some moths: females = XX, males = XO

• C. elegans (nematode): males = XO, but "XX" individuals are not females — they're self-fertilizing hermaphrodites (produce both eggs and sperm)

ZZ/ZW system (birds, butterflies), reverse matching/unmatched

• Males = ZZ (matching chromosomes)

• Females = ZW (unmatched)

• Heterogametic sex = the sex with two different sex chromosomes → produces two types of gametes (human males: X or Y gametes; female birds: Z or W gametes)

• Homogametic sex = the sex with two matching sex chromosomes → produces only one type of gamete (human females: only X; male birds: only Z)

No specialized sex chromosomes at all

• Bees and wasps: females are diploid, males are haploid (no chromosome-based sex determination — ploidy determines sex)

• Certain fish species: males and females have identical chromosome types/numbers — sex is determined by temperature (environmental sex determination — genes still control the process, but environment triggers which pathway runs)

Discovery of Sex Linkage by Morgan (white eyed and red eyed fruit flies)

F1 red-eyed males × F1 red-eyed sisters → F2

• Predicted: 3:1 red: white (standard Mendelian)

• Actual result: among red-eyed offspring, 2 females for every 1 male; all white-eyed offspring were male

• Key observation: eye color ratio differs between sexes — unlike Mendel's traits (which transmit equally to both sexes)

Crisscross Inheritance

• white-eyed female × red-eyed wild-type male

• Result: all red-eyed daughters, all white-eyed sons

• Called crisscross inheritance: sons inherit eye color from their mother; daughters inherit eye color from their father

• Reciprocal crosses (red female × white male vs. white female × red male) give different results — again, unlike Mendel

Morgan’s conclusion: the white eye gene is X-linked

• Carried on the X chromosome; the Y chromosome carries no allele for this gene

• Males are hemizygous for X-linked genes — they have only one copy (not two), since their single X comes from mom and their Y (no allele) comes from dad

• Notation: gene + chromosome together, e.g. X^(w+)Y (red-eyed male) vs. X^wY (white-eyed male)

Sex chromosome nondisjunction

• Rare failure of the X chromosomes to separate properly during meiosis in females

• Can occur during meiosis I or meiosis II

• Result: some eggs end up with two X chromosomes, others with no sex chromosome (0)

Transmission of the white alleles tracked exactly with the predicted behavior of X chromosomes during these rare meiotic errors

• Showing that specific genes really do physically reside on specific, identifiable chromosomes.

Why are X-linked recessive traits more common in men?

• Males are hemizygous for all X-linked genes — only one copy

• Males need only one recessive allele (from mother) to show the trait; females need two (one from each parent)

• SO X-linked recessive conditions (e.g., color blindness) are much more frequent in males

“Skip a Generation” Pattern

• Affected male → passes the X-linked recessive allele only to his daughters (his sons get his Y, not his X)

• Daughters are unaffected carriers (heterozygous)

• Carrier daughters can then pass the allele to their sons, who are affected

• Pattern: affected grandfather → carrier daughter (unaffected) → affected grandson

X-Linked Recessive Inheritance in a Pedigree

• More males than females affected (females need 2 copies; hemizygous males need only 1)

• Never passes father → son (son gets Y from dad, not X)

• Affected male → all daughters are carriers; each of their sons has a ½ chance of being affected

• Trait often skips a generation (grandfather → carrier daughter → grandson)

• Trait can appear in the same generation if a sister of an affected male is also a carrier — her sons each have ½ chance

• Rare homozygous affected female: ALL her sons affected, ALL her daughters carriers

X-Linked Dominant Inheritance in a Pedigree

• More females than males show the (rare) trait

• Seen in every generation as long as affected males have daughters

• Affected male → ALL daughters affected, NO sons affected (this is the single most useful clue for distinguishing X-linked dominant from autosomal dominant!)

• Affected female → sons and daughters each have ½ chance

• Carrier females can show a milder version than affected males, if incompletely dominant

Y-Linked Inheritance in a Pedigree

• Seen only in males

• All male descendants of an affected male show the trait (passes directly father→son→grandson, unbroken)

• Females never exhibit it AND never transmit it (they have no Y)

What problem requires Dosage Compensation?

• Problem: X chromosome carries 850 genes, XX females have two copies of each X-linked gene, while XY males have only one

  • Without correction, females would make double the gene product compared to males

Dosage Compensation & Barr Bodies

• XX cells inactivate one of their two X chromosomes

• Nearly all genes on the inactivated X are turned off — no gene product made

• Each cell randomly condenses one X into a Barr body, appears as a small, dark, condensed structure in interphase cells

• Also called lyonization

Barr Bodies are clonal, random, and independent; How?

• Each cell independently “chooses” which X to inactivate (maternal or paternal) — it's random per cell

• Choice is clonally inherited: every daughter cell descended by mitosis from that original cell inactivates the same X

• Result: adult human females are a mosaic/patchwork — some patches of cells express genes from the maternal X, other patches express genes from the paternal X

Equalizing dosage for PARs

• Recall: Two tips of X chromosome = PARs, PARs contains genes that are also present at the tips of the Y chromosome

• To equalize PAR gene dosage between XX and XY cells, the PAR genes on the Barr body X chromosome escape inactivation (i.e., even though the rest of that X is silenced, the PAR regions stay active)

How does equalizing the PAR gene dosage explain Aneuploidy syndromes (Klinefelter and Turners)?

• Klinefelter (XXY): One X becomes Barr body, 3 doses of PAR genes instead of 2 > Too much PAR gene product

• Turner (XO): A single X does NOT become Barr body, 1 dose of PAR genes instead of 2 (like in normal XX females) > Too little PAR gene product

• This mismatch in PAR gene dosage may explain these individuals have atypical morphological features, beyond just the effects of SRY presence/absence.

Dosage compensation strategies are different in different species (mammals, fruit flies, nematode)

• Goal: equalize X-linked gene dosage between sexes

• Mammals: turn one X off entirely

• Drosophila: hyperactivate the single male X by 2

• C. elegans: turn both hermaphrodite X's down to relatively match the single X in males

Y-Linked Traits are extremely rare

• Theoretically, mutations in the MSY region of the Y chromosome should be identifiable (in pedigrees) because they would only be passed down to all male descendants

• BUT: besides maleness itself and male fertility/sperm formation, no other clear-cut Y-linked visible traits have been found in humans

• Reflects correctly that the Y chromosome (specifically the MSY) has very few genes, which makes sense since XX females function well without a Y, meaning the Y has a very limited effect on phenotype

Autosomal genes can also cause sex differences (sexual dimorphism): Sex-Limited Traits

• Affect a structure/process found in only one sex

• Example: Drosophila — autosomal recessive mutation stuck affects males' ability to retract the penis and release claspers after mating → mutant males have trouble separating from females (extreme cases: both die, stuck together)

• Females are unaffected carriers phenotypically, since they lack the anatomical structures (penis, claspers) the gene acts on — even homozygous mutant females mate normally

Autosomal genes can also cause sex differences (sexual dimorphism): Sex-Influenced Traits

• Show up in both sexes, but expression differs by sex due to hormonal differences

• Example: pattern baldness in humans (loss of hair from the top of the head, not sides)

  • Heterozygotes: males go bald in their 20s; females show little/no hair loss

  • Homozygotes: both sexes go bald (though onset is later in homozygous females than homozygous males)

  • Net effect: the balding allele behaves as dominant in males, recessive in females — same genotype, different phenotypic outcome based on sex/hormones