Sex Chromosomes and Sex Linkage

Sex Chromosomes and Sex Determination

• In the late 19th and early 20th centuries, the difference in chromosome constitutions between males and females was noted, leading to the identification of sex chromosomes as sex-determining.
• The XY sex-determining system evolved independently from the ZW sex-determining system.
• Thomas Hunt Morgan mapped the first sex-linked trait (the white locus for eye color) to the X chromosome in Drosophila melanogaster and determined the genetics of sex in flies.

The Mammalian Y Chromosome and Sex Determination

• The Y chromosome is smaller than the X chromosome and is gene-poor.
• Small regions at the tips of the Y chromosome are homologous with the X chromosome, known as pseudoautosomal regions (PAR), which allow the X and Y chromosomes to pair and recombine during meiosis in the male.
• The gene SRY (Sex-determining Region Y gene) is necessary and sufficient to cause male development, encoding a transcription factor that activates a testis-forming pathway early in development.
• SRY is necessary for spermatogenesis, but other genes on the Y chromosome are also required.

X-Linked Traits

• In humans and other mammals, mutations in genes on the X chromosome result in abnormalities that are manifested differently between the sexes because males are hemizygous for the X.
• Dosage compensation between the mammalian sexes is achieved by inactivating one of the two X chromosomes.
• In males, the sole X remains active in every cell, and each daughter must receive her father's sole X chromosome.
• For X-linked recessive diseases, males manifest the disease, and rarely females, with no father-to-son transmission.
• Carrier females are usually asymptomatic, but a minority of carrier females may present with a mild form of the phenotype due to X inactivation.
• Around 515 X-linked recessive traits are known in humans, with varying frequencies in different ethnic groups.

X Inactivation and Dosage Compensation

• X inactivation is an epigenetic paradigm that normalizes the expression levels of X-linked genes between males and females.
• In abnormal cells with multiple X chromosomes, all but one is inactivated, and this applies to both male and female cells.
• Work by Mary Lyon established that the condensed chromosome observed in 46XX female cells was the inactive one, and that the cells retained a memory of which X was inactivated.
• Females are mosaic for genes on the X, with some cells expressing alleles from the paternally inherited X and others expressing alleles from the maternally inherited X.
• Some genes escape X inactivation, being expressed from both X chromosomes, often having copies on the Y chromosome.

Epigenetic Modifications and Genome Function

• Epigenetic modifications regulate a range of processes in mammalian cells, including chromosome architecture, silencing of repetitive transposable elements, and dynamic and somatically heritable changes in gene expression.
• Epigenetic modifications are chemical marks on the DNA (especially DNA methylation) and post-translational modifications to chromatin-associated histone proteins.
• DNA methylation occurs on CG dinucleotides and is symmetrical on the two DNA strands.
• Histone modifications are established by 'writers', interpreted by 'readers', and can be reversed by 'erasers'.
• Epigenetic modifications contribute to the architecture and function of the genome, and can be over short regulatory elements or over longer regions of DNA.