Sex Chromosomes and Linkage Notes

Theme 5, Module 3: Sex Chromosomes and Linkage

Learning Objectives

Understand the patterns of inheritance of genes on the X chromosome.
Recognize the linkage of genes along all chromosomes.
Interpret linkage maps for genes on a single chromosome.
Consider the value of genomic linkage maps based on genetic markers such as SNPs.

Introduction to Human Trait Inheritance

Studying human trait inheritance is complicated by:
- Humans producing few offspring.
- Ethical concerns about controlled breeding.
Geneticists use family history and pedigrees to study trait transmission.

Pedigrees

Males are represented by squares, females by circles.
Affected individuals are represented by shaded symbols.
Matings are illustrated as:
- A single horizontal line between unrelated individuals.
- Two horizontal lines between related individuals.
Progeny are arranged horizontally in order of birth (left to right).
Pedigrees can track dominant and recessive inheritance patterns.

Chromosomes and Genes

Humans have 23 pairs of chromosomes, containing over 3 billion base pairs of DNA.
Estimates suggest over 20,000 protein-coding genes and genes for functional RNA molecules.
There is more than one gene per chromosome.
Question: Are all alleles on a single chromosome inherited as a unit, or can they separate?
Phenotypic variation suggests alleles on a single chromosome can become unlinked and recombine.

Unit 1: Inheritance of Genes on the X Chromosome

Sex Chromosomes

Humans have two types of sex chromosomes: X and Y.
The Y chromosome is much smaller than the X chromosome.
Females have two X chromosomes (one from each parent).
Males have one X and one Y chromosome.
Most regions of the X and Y chromosomes are non-homologous (few genes in common).
Only small regions at the tips of the X and Y chromosomes allow for pairing and segregation during meiosis.
The human Y chromosome has 78 genes coding for about 25 proteins (half related to sex determination).
The X chromosome has approximately 1100 genes, many unrelated to sex determination.
A gene located on a sex chromosome is called a sex-linked gene.

Sex Determination

Genes on the sex chromosomes determine sex.
In humans, the presence of genes on the Y chromosome initiates male development.
Other autosomes are inherited in the same manner but are not directly involved in sex determination.
There is a 50% chance of a child being male (inheriting the Y chromosome from the father) and a 50% chance of being female (inheriting the X chromosome from the father).
The mother can only pass on an X chromosome.
Mendel’s principles do not fully apply to genes on the X and Y chromosomes because peas do not have sex chromosomes.

Inheritance of X-linked Traits

Pedigrees can trace the inheritance of alleles on the X chromosome.
Red/green color-blindness is an X-linked recessive trait.
The Ishihara color test is used to test for red/green color-blindness.
Heterozygous women are carriers and do not show the phenotype as it's recessive.
Homozygous recessive women will be color-blind.
A heterozygous mother can pass on the color-blindness allele to her offspring.
Males receiving the recessive allele from their mother are color-blind (hemizygous).

Hemizygosity

Males have only one locus for X-linked alleles (hemizygous).
The rule of dominance/recessiveness does not apply in hemizygous individuals.
Males express the phenotype associated with the one allele they carry on their X chromosome.

Punnett Square Analysis of X-linked Inheritance

A female carrier has a 50% chance of passing on the affected allele.
Males inheriting the affected allele will be color-blind.
Females can inherit the affected allele and become carriers (50% probability).

Tracing Carriers in Pedigrees

Females can be carriers across many generations without showing the phenotype.
Haemophilia is an X-linked recessive trait due to a mutation in a gene encoding a blood-clotting protein.
Queen Victoria was a carrier for haemophilia.
Pedigrees indicate carrier females who are heterozygous but do not show the phenotype.

Haemophilia in the British Royal Family

Punnett square analysis of Queen Victoria and Prince Albert's offspring:
- 50% of females will be carriers for haemophilia.
- 50% of males will be normal.
- 50% of males will have haemophilia.
It is unusual for females to be affected by haemophilia, as they need to inherit the affected allele from both parents.
The mutant allele is no longer present in the current British Royal family because King Edward VII (Queen Victoria’s son) was not affected.

Unit 2: Genetic Linkage

Mendel's Second Law vs. Linked Genes

Mendel’s second law: two genes sort independently during gamete formation.
What if genes are physically linked on the same chromosome?
Example: Human X chromosome (155 million base pairs, ~1100 genes).
Genes close together on the same chromosome are called linked genes.
Linked genes tend to be inherited together and do not segregate independently.
Example: genes for color-blindness and haemophilia.
Question: Are linked genes always inherited together?

Breaking Linkage

Linked genes are not always inherited together.
Linkage can be broken during prophase I of meiosis through chiasmata or crossovers.
Recombination events can separate alleles of neighboring linked genes.
Offspring may inherit only one of the genes due to recombination.

Recombination of Alleles

Gene position does not change, but allele association does.
If genes are far apart, crossovers generate recombinant chromatids with alternate allele combinations.
Example: Genes A and B with alleles A/a and B/b.
- Parental chromosomes: AB and ab.
- Crossover creates recombinant gametes: Ab and aB.
If genes are immediately adjacent, crossing over is unlikely in the region between them.
Recombination frequency depends on the distance between genes.
- Closer genes show less recombination.
- Genes farther apart show higher recombination.
Recombination frequency can be used to determine the distance between genes on the same chromosome.

Unit 3: Constructing Linkage Maps

Genetic distance

Genes in close proximity on the same chromosome are inherited together.
Pedigree analysis of colour-blindness and haemophilia shows linkage.
Exception: individual with only haemophilia implies separation by crossing over/recombination.
Frequency of exceptions indicates distance between genes.
Relative distance allows researchers to create a linkage map.
Example: colour-blindness and haemophilia are roughly 12 map units (centimorgans) apart on the X chromosome which is about 12 million base pairs.

Applying SNPs to linkage maps

Human linkage maps are less practical, genes can lie millions of base pairs apart and need a visible phenotype.
Can use millions of SNPs and other markers in non-coding regions to create high-density maps that are a few thousand base pairs apart.
Linkage maps can map human genes that determine various characteristics.
Frequency of recombination reveals relative distance between genetic loci (genes, markers, or gene marker).
Gene distant from marker: Recombination always occurs and allele combinations are equally represented (25% each) and there is no association
Gene close to marker: Combination isn't always equal and recombination will be rare and the distance between is relatively small and there is an association

Genome-Wide Association Studies (GWAS)

Pedigree analysis is limited to related individuals.
SNP-linkage maps and technology allow researchers to study many unrelated individuals.
GWAS looks across entire SNP-linkage map for association between phenotype and mapped SNP.
Example: Association between height and a particular marker allele led to identifying HMGA2 gene that contributes to less than 1 cm variation in height.
- Individuals with two “C” alleles of HMGA2 are 0.8cm taller than people with two “T” alleles.
- Individuals heterozygous for the “C” and “T” alleles are only 0.4cm taller than people with the two “C” alleles.
Association studies help identify genes contributing to human characteristics, including diseases.

Module Summary

Genes on the X chromosome have a 50% chance of a child being male and a 50% chance of a child being female.
Mendel’s second law is not always applicable and genes close together on the same chromosome are inherited together.
Crossovers between genes on a chromosome dictate how far they are from each other allowing the creation of linkage maps.
Linkage maps can be made with the use of specific DNA markers throughout our genome to allow the creation of high density linkage maps.