Chapter 4

Sex Linkage and Pedigree Analysis

Sex Linkage
Autosomes
- all homologous pairs of chromosomes not including the sex chromosomes

Sex chromosomes
- heteromorphic chromosomes whose distribution in a zygote determines the sex of an organism

Sex linkage
- Genes that are located on the sex chromosomes and their inheritance

Sex Linkage
Inheritance patterns : X linked recessive alleles
1) males exhibit X linked recessive phenotype - females are homozygous or heterozygous - males are hemizygous : some genes are present in only 1 copy - pseudodominance : a single recessive allele can determine a phenotype

2) crisscross pattern of inheritance - father transmits allele to daughter (carrier) - mother transmits phenotype to son

Inheritance of an X-linked Recessive Trait: Is Homozygous or Heterozygous

a.

parent : homozygous dominant all offspring dominant

b.

parent : heterozygous,

dominant

offspring exhibit recessive trait

Inheritance of an X-linked Recessive Trait: Is Heterozygous or Recessive

(Deviation from Mendelian pattern of dominance switching dominant or recessive parent in a and d gives different results)

c.

parent heterozygous, all and

recessive

exhibit the recessive trait

d. parent recessive, dominant

are recessive, all exhibit

dominant trait

Sex Linkage
Y linked traits: found only in males (holandric) Sex-limited trait: expressed in only 1 gender, but the genes are found in both (autosomal)
- breasts, milk in women ; facial hair, sperm in men

Sex-influenced trait: appears in both genders, but dominant in one and recessive in other (autosomal)
- long QT syndrome more females than males, but gene is on an autosome (may be hormonal contributions)

Pseudoautosomal : found on both sex chromosomes

Morgan and Bridges Experiments :

Proving the Chromosomal Theory of Inheritance

Isolation of a White-Eyed Mutant in a Culture of Wild-Type Flies (Red Eyes)

observations of Thomas Hunt Morgan : flies with white eyes P1 cross: Wild-type F1 progeny: and are all Red eyed (wild type) x White-eyed

F1 progeny crossed Red-eyed and white-eyed flies -not equally distributed between the sexes : all had red eyes ; : had red eyes , had white eyes

Wild-Type x White-Eyed : The Alleles for White Eye Are on the X Chromosome
we know that females have 2 X chromosomes and males have 1 X and 1 Y chromosome, so :

w allele on X chromosome probably accounts for results

The Reciprocal Cross: White-Eyed x Wild-Type

Morgan switched the phenotypes of the parents :

F1 progeny all are white-eyed all are red-eyed

Crisscross pattern of inheritance

in F1
female passes her phenotype to her sons male passes his phenotype to his daughters very likely that white eye color phenotype is associated with X chromosome, still not proven

Pattern of Inheritance of the White-Eyed Trait in Drosophila

Calvin Bridges experiments that proved the chromosomal theory of inheritance : - used very large numbers of progeny

1/2000

F1 progeny: crisscross pattern of inheritance demonstrated Exception observed 1/2000 were red-eyed and 1/2000 were white-eyed were fertile Primary exceptional progeny:

were sterile,

The Primary Exceptional (White-Eyed) Is Fertile and Is Crossed with Red-Eyed

1/200

The majority of the progeny were white-eyed However: 1/200 had red eyes 1/200 had white eyes Secondary exceptional progeny and both fertile

and red-eyed

P1 Cross: Observation of Primary Exceptional Progeny

The logic of gender

Bridges Model :

Bridges knew that : have only 1 X chromosome without a Y chromosome were sterile

Primary exceptional : X0 and were sterile

F1 Crosses to Yield the Secondary Exceptional Progeny

Primary exceptional received the X chromosome from the parent (because they had red eyes) and no sex chromosome (0) from the parent Genetic balance in Drosophila for X0: offsprings X:A: ratio would be 0.5 and the fly would be

Explanation : Nondisjunction
Chromosomes do not segregate during meiosis I or meiosis II
Sperm with an X chromosome could fertilize an egg lacking an X chromosome XO Primary exceptional female is XXY : sperm with Y chromosome fertilized egg with 2 X chromosomes

* both events : very low frequency (~1/2000)

Cytology studies confirmed the hypothesis that they were XO proved chromosomal theory of inheritance: chromosomes are tightly associated with genetic units that give a certain phenotype

Chromosomal Theory of Inheritance

Bridges used Drosophila mutants that experienced nondisjunction to predict the correct combination of sex chromosomes that corresponded to a specific eye color

chromosomal theory of inheritance : Bridges : chromosomes are tightly associated with genetic units that give a certain phenotype Modern view : genes are linear sequences of DNA on chromosomes

Nondisjunction in original female parent:

(normal)

Nondisjunction in the white-eyed Primary Exceptional

(more numerous because of homologous chromosome pairing)

Sex Determination
XY system in humans (46 chromosomes, 23 homologous pairs)
- females (XX) are homogametic : 2 copies of the same sex chromosome - males (XY) are heterogametic : gametes have either X or Y chromosome SRY (sex-determining region Y) gene on Y chromosome determines maleness - lack of SRY determines femaleness (XX + SRY is male)

Human Karyotype

: 23 homologous pairs = homogametic sex (XX) : 22 homologous pairs + 1 heterologous pair = heterogametic sex (XY)

The Human Y Chromosome

Contains 171 genes A single gene determines if a developing mammal will be male - Sex-determining region Y (SRY) on Y chromosome - Switch to initiate male development - XX + SRY gene : male Pseudoautosomal region allows the Y chromosome to pair with the X chromosome during meiosis

A Nondisjunction event can produce gametes that contain an extra copy of a chromosome or lack a chromosome
Results: i. polyploid (extra set of chromosomes : 3n, 4n . . . ) ii. aneuploid (additions or deletions of individual chromosomes)
Turner syndrome : X0, female

Klinefelter syndrome : XXY, male

Genic Balance in Drosophila - Sex Is Determined

by the Ratio of X Chromosomes that Favor Femaleness : Autosomes that Favor Maleness

X:A 1.00 : female X:A 0.50 : male

X:A = 0.67 : intersex X:A = 0.33 : metamale X:A = 1.50 : metafemale

Systems of Gender Determination

ZW system, are the homogametic sex (ZZ) and are the heterogametic sex (ZW) C. elegans (nematode) : X0 system hermaphrodite : XX ; both sex organs

Temperature Can Have Effect on Gender Determination

Environmental Sex Determination: Varies from species to species Low temperatures some organisms develop only as others develop as while

Gene Balance
Sex-linked genes : located on sex chromosomes (X-linked if X chromosome involved) 2 genders often differ in # of 1 or more chromosomes Dosage compensation : balancing gene expression of sex-linked genes in different genders

Detection of Male-Specific Lethal-2 (MSL-2) Protein in Drosophila

In order to attain gene balance : : X-linked genes are hypertranscribed relative to the Increased transcription requires 4 proteins encoded by : Maleless and male-specific lethal (MSL)-1, -2, & -3 Mutations in any of the above genes results in the dying early in development Localization of the MSL-2 protein is evident on the X chromosomes in the but not in the
females

chromosomes

MSL-2

males

X Chromosome Inactivation in mammals

for dosage compensation, all X chromosomes in the cell (except one) are modified such that they are transcriptionally inactive Results in normal , , and Klinefelter exhibiting the same level of expression Inactivated X chromosome = Barr bodies Only part of the X chromosome is inactivated -

Genes in the pseudoautosomal regions and select others remain active in the Barr body

X Chromosome Inactivation in Mammals: Barr Bodies

(present in every normal female cell in mammals)

X Chromosome inactivation is random in mammals

red : maternal blue : paternal

Once an X chromosome is inactivated in a cell, all descendents will have the same X chromosome inactive Occurs in embryo (64-1000 cells)

Results in mosaic
Patches or regions will appear differently depending if the cells present have an active paternal or maternal X chromosome the Calico cat

Human Genetics
Humans take a long time to reach sexual maturity, do not produce many offspring, and cannot be used for experiments Pedigree : representation of individuals and their phenotypes in several generations of a family gives mode of inheritance and genotypes, help parents decide genotype of offspring - assumptions : i. trait being examined is rare ii. persons marrying into the family lack the trait

Symbols used in pedigree analysis

Arrow points to proband : individual 1st identified with the trait

Questions to ask in pedigree analysis

Does the trait occur in every generation ? dominant vs. recessive Number of affected males and females ? sex-linked or autosomal

Inheritance of Polydactyl: An Autosomal Dominant Trait

Different symbols are used in this pedigree

Siblings are numbered according to birth order

Generations are numbered on the left in Roman numerals

The Inheritance of Hypotrichosis (lack of hair growth):an autosomal recessive trait

Note that two unaffected individuals (III-1, III-2) have some affected children, suggesting a recessive trait

Inheritance of Vitamin-D Resistant Rickets

Examination of this pedigree: Affected passing trait to their daughters, not sons

Consistent with transmission on the X chromosome

Represents most likely a sex-linked dominant trait * rule out sex-linked if father passes trait to his son

Pedigree Showing the Inheritance of Hemophilia in the Ancestors of Queen Victoria

General Patterns of Inheritance

Autosomal dominant 1) should not skip generations 2) unaffected + affected parent : 50% of offspring are affected 3) equal numbers in males and females Autosomal recessive 1) skips generations 2) equal numbers in males and females 3) traits often found in offspring of consanguineous matings 4) both parents affected : all children affected 5) most cases : unaffected + affected parent : all children unaffected 6) most affected individuals : unaffected parents/carriers

General Patterns of Inheritance

Sex-linked dominant 1) should not skip generations 2) affected males from affected mothers 3) half the children (male and female) of het. female have trait 4) affected females : affected fathers or mothers 5) all daughters, but no sons, of affected father have trait Sex-linked recessive 1) most affected individuals are male 2) all daughters of affected male are carriers ; sons not affected 3) affected females : affected fathers and affected or carrier mothers 4) all sons of affected females have trait 5) the sons of carrier females have trait

Genotypes Can Be Deduced from Pedigrees

Inheritance of a recessive trait III-2 and III-5 are affected but their parents are not Affected children are the majority are not and

Indicates an autosomal recessive trait

Assign genotypes

I-1: homozygous dominant (RR) I-2: homozygous recessive (rr)

II-2 and II-3 must be heterozygotes Deduce the other genotypes