MBGE 206 Sex Chromosomes

Pseudoautosomal regions

regions that are homologous to both sex chromosomes (X/Y).

Significance of PAR regions

The pseudoautosomal regions (PARs) of the Y chromosome undergo meiotic recombination with the X-chromosome. PAR mutations are associated with infertility and mental and stature disorders. PAR1 has a required cross over for successful sperm development

Genes in PAR1

Region at the tips of their short arms (PAR1). This region is known as the major pseudoautosomal region and genes in this area are not subject to inactivation and they obligatory crossover resembling normal autosomal genes

PAR2 region

region of homology between X & Y exist at the tip of their long arms but pairing and crossing over is not obligatory

X chromosome

very similar to autosomes; many genes, mostly un-related to sex

Dosage compensation in Drosophila

A complex with at least one male-specific gene binds to the X chrosome altering its sturcture. Acetylation of the X chromosome increases trasncriptional activity and brings it to the same elvel as the 2X chromosomes in females.

Dosage compensation in C elegans

In females of C.elegans the complex decreases the level of transcription of each chromosome by half

X chromosome inactivation

In mammalian females, one of the two X chromosomes in each cell is randomly inactivated during embryonic development. The inactive X condenses into a Barr body. If a female is heterozygous for a particular gene located on the X chromosome, she will be a mosaic for that character

Lyon hypothesis:

Placental mammals randomly inactivate all but 1 X at the 200-400 cell embryo stage (blastocyst)

Barr bodies

late replicating condensed chromatin sitting on the nuclear membrane (heterochromatin).

X inactivation center (Xic)

The X-inactivation center (XIC) on the X chromosome is necessary and sufficient to cause X-inactivation. Chromosomal translocations which place the XIC on an autosome lead to inactivation of the autosome, and X chromosomes lacking the XIC are not inactivated. The XIC contains non-translated RNA gene, Xist which are involved in X-inactivation. The XIC also contains binding sites for both known and unknown regulatory proteins

Xist

a gene in the XIC region which is expressed only from the INACTIVE X. It has 8 exons, but it codes for structural RNA (not mRNA). XIST encodes a large molecule of RNA Barr bodies are inactive X chromosomes "painted" with XIST RNA

Genes on X that are not inactivated

Genes in pseudo-autosomal regions PAR1 and PAR2. The genes of pseudoautosomal regions of the Xi do not have the typical modifications of the Xi and have little Xist RNA bound

SMC (Structural Maintenance Chromosome)

proteins are ATPases that include condensins and cohesins

Function of condensins

Condensins cause chromatin to be more tightly coiled by introducing positive supercoils into DNA. Condensins are responsible for condensing chromosomes at mitosis. Chromosome-specific condensins are responsible for condensing inactive X chromosomes in C. elegans.

Conditions for survival during imprinting

When genes are differentially imprinted, survival of the embryo depends on whether a functional allele is provided by the parent with the unmethylated allele

DNA methylation

Paternal and maternal alleles may have different patterns of methylation at fertilization. Methylation is usually associated with inactivation of the gene

key gene in Y chromosome

The key gene is SRY “Testis determining factor” TDF. SRY includes a single exon that acts as a transcription factor. Works by binding to DNA and distorting its shape.

Y chromosome

mostly inert, very few genes, mostly repeat sequence DNA (high and middle). Encodes 26 distinct proteins many of them are important for male Fertility

Comparison of X and Y genes throughout time

From a comparison of the genes on the X and Y chromosomes, we can infer that, even though the X is now much larger than the Y, 300 million years ago they were essentially identical

Muller’s ratchet

Proto-X and proto-Y were a pair of ordinary autosomes in the common ancestor of mammals and birds. Y chromosome started out as normal chromosome with many genes. But, without crossing over, mutations built up and inactivated most genes

Origin of Y

Muller’s ratchet + Once SRY had evolved as a sex-determining mechanism, the Y chromosome began to diverge in DNA sequence from the X chromosome, the region of possible X-Y recombination become progressively restricted to the telomeric regions. In the region with no X-Y recombination, multiple deleterious mutations accumulate without an opportunity for recombination to regenerate Y chromosomes. Blocks of genes were removed from the region of X-Y recombination in large chunks including other rearrangements such as inversion

How can Y chromosome be utilized for phylogenetic trees?

Y chromosomes does not undergo recombination: 5% recombines with X chromosome (PAR region) 95% non-recombining region There is less variation on the Y chromosome than the autosomes. By sampling the Y chromosomes from different populations, it is possible to construct a phylogenetic tree of Y chromosome evolution in human

Deletion Hybridization

It was found by studying a human XY female. It turned out that she had a deletion in the Y chromosome that did not allow male traits development

Evidence for Sry being the determining factor for males

1) XY patients who are female have mutations in the SRY region. 2) A mutant line of mice with XY females has deletion of corresponding Sry gene 3) take fertilized mouse embryos, mixture of XX and XY, inject with many copies of cloned and purified mouse Sry gene. implant embryos back in mothers. gene will be incorporated into genome and expressed in some but not all baby mice,-produced 2 XX male mice. These were Sry transgenic but also sterile because lacked other missing Y genes.

Inversion

the process of rearranging genetic material within a genome, resulting in a changed orientation of a chromosomal segment or a gene