Unit 5: Sex Determination and Population Genetics - Subjective Questions

In mammals, sex is determined by the XX-XY chromosomal mechanism:

• Females are homogametic (XX) and produce only X-bearing eggs.
• Males are heterogametic (XY) and produce two types of sperm (X-bearing and Y-bearing).

Role of the Y chromosome:

• The Y chromosome carries the SRY gene (Sex-determining Region Y), located on the short arm.
• SRY encodes the TDF (Testis Determining Factor), which triggers the undifferentiated gonad to develop into testes.
• Testes secrete testosterone and Anti-Müllerian Hormone (AMH), promoting male differentiation.
• In the absence of SRY (XX individuals), the gonad develops into an ovary, leading to female development.

Key evidence:

• XXY (Klinefelter) individuals are male → Y determines maleness.
• XO (Turner) individuals are female → maleness depends on Y, not the number of X chromosomes.

Thus, in mammals the Y chromosome is the dominant determinant of sex.

In Drosophila, sex is determined by the X:Autosome (X:A) ratio, proposed by Calvin Bridges as the Genic Balance Theory.

Principle:

• Sex depends on the ratio of the number of X chromosomes to the number of sets of autosomes (A), NOT on the Y chromosome.

X:A ratios and resulting sex:

Role of Y chromosome:

• The Y chromosome is NOT sex-determining; it is required only for male fertility (sperm formation).
• An XO fly is a sterile male.

Difference from mammals:

• In mammals, the Y chromosome (SRY gene) determines maleness.
• In Drosophila, the X:A ratio determines sex, and Y is irrelevant for sex determination.

Birds follow the ZW-ZZ mechanism of sex determination, which is the opposite of mammals.

System:

• Males are homogametic (ZZ) — produce only Z-bearing sperm.
• Females are heterogametic (ZW) — produce two types of eggs (Z-bearing and W-bearing).

Key points:

• The female determines the sex of the offspring (heterogametic sex).
• The DMRT1 gene on the Z chromosome plays a major role; higher dosage (ZZ) promotes male development.
• The W chromosome may carry female-determining factors.

Crosses:

Significance:

• Found in birds, some reptiles, and Lepidoptera (butterflies/moths).
• To distinguish from mammalian XY, the letters Z and W are used.

Fishes exhibit the most diverse and flexible sex-determination mechanisms among vertebrates.

Major mechanisms:

• Genetic Sex Determination (GSD):

  • XX-XY system (e.g., guppy, medaka)
  • ZZ-ZW system (e.g., some tilapia species)
  • Polygenic/multifactorial systems involving several genes.

• Environmental Sex Determination (ESD):

  • Temperature-dependent sex determination (e.g., Atlantic silverside).
  • pH, social factors, and density can influence sex.

• Hermaphroditism:

  • Sequential hermaphroditism — sex change during life:
  • Protogyny (female → male, e.g., wrasses).
  • Protandry (male → female, e.g., clownfish).
  • Simultaneous hermaphroditism — both sexes at once.

• Environmental + Genetic interaction in some species.

Why diverse?

• Fishes have labile gonads and lack a strict genetic master switch in many species.
• Ecological adaptation, evolutionary flexibility, and absence of well-differentiated sex chromosomes allow multiple strategies to coexist.

Sex differentiation is the developmental process by which the undifferentiated embryo develops into a male or female phenotype after genetic sex is established.

Stages of differentiation:

1. Undifferentiated (bipotential) stage: The embryo has both Müllerian ducts (female) and Wolffian ducts (male) with an indifferent gonad.

2. Gonadal differentiation:

   • SRY present → testes develop.
   • SRY absent → ovaries develop.

3. Hormonal control:

   • Testosterone → develops Wolffian ducts (vas deferens, epididymis).
   • AMH (Anti-Müllerian Hormone) → causes regression of Müllerian ducts.
   • DHT (dihydrotestosterone) → develops external male genitalia.
   • In females, absence of these hormones allows Müllerian ducts to form the uterus, oviducts, and vagina.

Primary vs Secondary sexual characteristics:

Barr bodies are darkly staining, condensed masses of chromatin found in the nuclei of somatic cells of female mammals, discovered by Murray Barr and Bertram (1949).

Formation:

• In females (XX), one X chromosome is randomly inactivated during early embryonic development.
• The inactivated X becomes highly condensed (heterochromatin) and is visible as the Barr body.

Lyon Hypothesis (Mary Lyon, 1961):

1. One of the two X chromosomes in female mammals is inactivated.
2. Inactivation is random (either maternal or paternal X).
3. It occurs early in embryonic development and is permanent/heritable in daughter cells.
4. This achieves dosage compensation between males (XX) and females (XX).

Number of Barr bodies rule:

Significance:

• Used in sex verification (e.g., in sports).
• Diagnosis of chromosomal abnormalities.
• Explains mosaicism in females (e.g., tortoiseshell cats).

Dosage compensation is a mechanism that equalizes the expression of X-linked genes between the two sexes despite the difference in the number of X chromosomes.

Need: Females (XX) have twice the X-linked genes compared to males (XY). Dosage compensation ensures equal gene product levels.

Mechanisms in different organisms:

• Mammals (e.g., humans):

  • One X chromosome is inactivated in females (forms the Barr body).
  • Both sexes express genes from only one active X.
  • Controlled by the XIST gene.

• Drosophila:

  • The single X in males is hyperactivated (upregulated ~2-fold).
  • Mediated by the MSL (Male-Specific Lethal) complex and roX RNAs.

• Caenorhabditis elegans:

  • Hermaphrodites are XX, males are XO.
  • Both X chromosomes in the hermaphrodite are downregulated by half (partial repression).
  • Controlled by the Dosage Compensation Complex (DCC).

Summary table:

Hardy-Weinberg Law (independently proposed by G.H. Hardy and Wilhelm Weinberg in 1908) states that in a large, randomly mating population, the allele and genotype frequencies remain constant from generation to generation in the absence of evolutionary influences.

Mathematical expression:

For two alleles A (frequency ) and a (frequency ):

Genotype frequencies:

where:

• = frequency of homozygous dominant (AA)
• = frequency of heterozygous (Aa)
• = frequency of homozygous recessive (aa)

Assumptions/Conditions:

• Large population size — to prevent genetic drift.
• Random mating — no mate preference (panmixia).
• No mutation — allele frequencies not altered by mutation.
• No migration — no gene flow (immigration/emigration).
• No natural selection — all genotypes equally fit and survive equally.

Significance:

• Serves as a null model to detect evolution.
• Deviation from equilibrium indicates that evolutionary forces are acting on the population.

Given:

• Total individuals = 1000
• Individuals showing recessive trait (aa) = 160

Step 1: Frequency of homozygous recessive genotype ():

Step 2: Frequency of recessive allele ():

Step 3: Frequency of dominant allele ():

Step 4: Genotype frequencies:

• AA = → individuals
• Aa = → individuals
• aa = → individuals

Results:

Verification: ✓

Mutation is the ultimate source of new alleles and is a fundamental force in altering allelic frequencies.

Effect of mutation:

• Forward mutation: at rate
• Reverse mutation: at rate

Mutations change allele frequencies slowly because mutation rates are low ( to per generation).

Change in allele frequency:

Let = frequency of A, = frequency of a.

Change in per generation:

Equilibrium condition:

At equilibrium, forward and reverse mutations balance each other, so :

Substituting :

Equilibrium allele frequencies:

Conclusion:

• Equilibrium depends only on the ratio of mutation rates.
• Mutation alone causes very slow changes and rarely determines evolution independently.

Migration (gene flow) refers to the movement of individuals (and their alleles) between populations, which alters allelic frequencies of the recipient population.

Effects:

• Introduces new alleles into a population.
• Reduces genetic differences between populations.
• Prevents populations from diverging (counteracts drift and selection).

Derivation:

Let:

• = frequency of allele in the native (recipient) population
• = frequency of allele in the migrant population
• = proportion of migrants entering the population per generation

After migration, the new allele frequency () is:

Change in allele frequency ():

Interpretation:

• The change depends on the migration rate () and the difference in allele frequencies between the two populations.
• If , then (no change).
• Migration continues until frequencies equalize.

Natural selection is the differential survival and reproduction of individuals due to differences in phenotype, resulting in changes in allele frequencies over generations.

Concept of fitness:

• Fitness (w) = relative reproductive success of a genotype.
• Selection coefficient (s) = reduction in fitness, where .

Types of selection:

1. Directional Selection:

   • Favors one extreme phenotype.
   • Shifts allele frequency in one direction.
   • Example: Industrial melanism in peppered moth (Biston betularia).

2. Stabilizing Selection:

   • Favors the intermediate phenotype; eliminates extremes.
   • Reduces variation.
   • Example: Human birth weight (intermediate weights survive best).

3. Disruptive (Diversifying) Selection:

   • Favors both extremes against the intermediate.
   • Can lead to speciation.
   • Example: Beak size in Darwin's finches during varied food availability.

4. Balancing Selection:

   • Maintains multiple alleles (heterozygote advantage).
   • Example: Sickle-cell allele maintained in malaria-endemic regions.

Effect: Selection is the primary force producing adaptation and directional evolutionary change in populations.

Genetic drift is the random fluctuation in allele frequencies from generation to generation due to chance events, especially in small populations.

Key features:

• More pronounced in small populations.
• Random (non-adaptive) — may fix or eliminate alleles by chance.
• Reduces genetic variation over time.
• Can lead to fixation () or loss () of alleles.

Special cases of genetic drift:

1. Bottleneck Effect:

   • A drastic reduction in population size due to catastrophes (disease, natural disaster, hunting).
   • The surviving population may have allele frequencies very different from the original.
   • Genetic diversity is greatly reduced.
   • Example: Cheetahs show very low genetic diversity due to a past bottleneck; Northern elephant seals (hunted to ~20 individuals).

2. Founder Effect:

   • A small group separates from a large population to establish a new population.
   • The new population's gene pool reflects only the founders' alleles, not the parent population.
   • Example: Amish population in the USA — high frequency of Ellis-van Creveld syndrome; high incidence of certain disorders on isolated islands.

Significance:

• Important in evolution of small/isolated populations.
• Can cause loss of beneficial alleles and fixation of harmful ones.

Genotypic frequency and allelic frequency are fundamental measures in population genetics.

Genotypic Frequency:

• The proportion of a particular genotype in a population.
  

Allelic (Gene) Frequency:

• The proportion of a particular allele among all alleles at a locus in the population.
  

Calculation of allele frequency from genotypes:

For a gene with alleles A and a:

where are numbers of each genotype and = total individuals.

Example: In 100 individuals: 40 AA, 40 Aa, 20 aa.

Key difference: Genotypic frequency describes combinations of alleles, while allelic frequency describes individual alleles.

Both mammals and Drosophila use the XX-XY chromosomal system, but the determining factor differs fundamentally.

Comparison:

Evidence from chromosomal abnormalities:

Mammals:

• XXY (Klinefelter): Male (Y present) — shows Y determines sex.
• XO (Turner): Female (no Y) — one X alone gives female.
• XYY: Male.

Drosophila:

• XXY: Female (X:A = 2:2 = 1.0) — Y ignored.
• XO: Male (sterile) (X:A = 1:2 = 0.5) — Y needed only for fertility.
• XXX (3X:2A = 1.5): Metafemale.

Conclusion:

• In mammals, presence/absence of Y decides sex.
• In Drosophila, the balance between X and autosomes decides sex.
• The same karyotype (e.g., XXY) gives opposite sexes in the two organisms.

SRY (Sex-determining Region Y) is the master gene for male sex determination in mammals, located on the short arm (Yp) of the Y chromosome.

Function:

• SRY encodes the TDF (Testis Determining Factor), a transcription factor with an HMG-box DNA-binding domain.
• TDF activates downstream genes (e.g., SOX9) that direct the bipotential gonad to develop into testes.
• Testes then produce testosterone and AMH, driving male development.

Consequences of SRY translocation/mutation:

1. XX males (de la Chapelle syndrome):

   • SRY is translocated to an X chromosome during abnormal crossing over in meiosis.
   • The individual is chromosomally XX but phenotypically male (sterile).

2. XY females (Swyer syndrome):

   • The Y chromosome carries a mutated/non-functional SRY or SRY is lost/translocated away.
   • The individual is chromosomally XY but phenotypically female (with underdeveloped gonads).

Significance:

• Confirms SRY is necessary and sufficient to initiate male development.
• Experimentally, transgenic XX mice carrying SRY develop as males, proving its role.

Selection against a recessive allele (aa) reduces its frequency because recessive homozygotes have lower fitness.

Setup:

where = selection coefficient against aa.

Mean fitness of population:

New frequency of allele a after selection ():

Change in allele frequency ():

Why complete elimination is difficult:

• As becomes small, becomes very small, so most recessive alleles are hidden in heterozygotes (Aa).
• Heterozygotes are not selected against, so they shelter the recessive allele.
• Therefore, becomes extremely small at low frequencies, and complete removal takes an enormous number of generations (approaches zero asymptotically but never reaches it).

X-chromosome inactivation (Lyonization) is the process by which one of the two X chromosomes in female mammals is randomly and permanently inactivated to achieve dosage compensation.

Mechanism:

• Occurs early in embryonic development.
• Controlled by the X-inactivation center (XIC) and the XIST gene, which produces a non-coding RNA that coats and silences one X chromosome.
• The inactivated X condenses into a Barr body.
• Inactivation is random but the same X remains inactive in all descendant cells (clonal).

Mosaicism:

• Because inactivation is random, a female is a mosaic — some cells express the maternal X and others the paternal X.
• This creates patches of tissue with different gene expression.

Tortoiseshell / Calico cats example:

• The gene for coat color (orange vs black) is X-linked.
• A heterozygous female (one X with orange allele, one X with black allele):
  • In some skin patches, the X carrying orange is active → orange fur.
  • In others, the X carrying black is active → black fur.
• Results in a characteristic patchwork (mosaic) coat.
• Note: Tortoiseshell cats are almost always female, since males (XY) have only one X. Male tortoiseshells are rare and usually XXY (Klinefelter).

Heterozygote advantage (overdominance) occurs when the heterozygote (Aa) has higher fitness than either homozygote, leading to the maintenance of both alleles in a population — a form of balancing selection.

Sickle-cell example:

The gene for haemoglobin has two alleles:

• (normal)
• (sickle-cell)

Explanation:

• In malaria-endemic regions (e.g., sub-Saharan Africa), the heterozygote () is protected from severe malaria AND does not suffer full-blown anaemia.
• Thus, heterozygotes have the highest fitness.

Maintenance of polymorphism:

• Because heterozygotes are favored, both alleles are retained in the population.
• Selection prevents either allele from being lost, maintaining a stable equilibrium (balanced polymorphism).
• This explains why the harmful allele persists at high frequency in malarial regions despite the lethality of the homozygous condition.

The Hardy-Weinberg (H-W) principle provides a null (baseline) model describing a non-evolving population. By comparing observed genotype frequencies with H-W expected frequencies, we can detect evolution.

How it detects evolution:

• If observed genotype frequencies match → population is in equilibrium (not evolving at that locus).
• If observed frequencies deviate significantly (tested by Chi-square test) → one or more evolutionary forces are acting.

Factors causing deviation from equilibrium:

1. Mutation:

   • Creates new alleles, slowly altering allele frequencies.

2. Migration (Gene Flow):

   • Introduces or removes alleles between populations, altering frequencies.

3. Genetic Drift:

   • Random change in small populations; can fix or lose alleles.

4. Natural Selection:

   • Differential survival/reproduction changes genotype and allele frequencies.

5. Non-random Mating (e.g., inbreeding, assortative mating):

   • Alters genotype frequencies (increases homozygotes) though allele frequencies may stay the same.

Significance:

• The H-W law itself is not a description of real populations but a theoretical reference.
• Deviations reveal the evolutionary forces operating, making it a powerful analytical tool in population genetics.