THE HUMAN GENOME: KARYOTYPES & VARIATIONS
1. What is "X chromosome inactivation",
and how does it affect phenotype?
Since women have two X chromosomes, while men have just one, there is the potential problem of "too much expression of X genes" in women. So, some form of "dosage compensation" is needed, and in mammals the system that has evolved is "X chromosome inactivation" during embryological development, as shown in Figure 8.7. The molecular mechanism of this phenomenon has been worked out within the past few years, and is described in the textbook as follows: (pages 302-3).
"The inactivation process is one of chromosome condensation initiated at a site called XIC (for X-inactivation center) near the centromere on the long arm. ... .... XIC includes a transcribed region in band Xq13 designated Xist (for X-inactivation-specific transcript). Transcription of Xist is the earliest event observed in X inactivation, and Xist is the only gene known to be transcribed only from the inactive X chromosome. Remarkably, the spliced transcript of Xist does not contain an open reading frame encoding a protein. It (rather) functions as a structural RNA, and as transcription of Xist continues, the spliced transcript progressively coats the inactive X chomosome, spreading outward from the XIC. Thereafter, other molecular changes take place along the inactive X chromosome that are typically associated with gene silencing. ..... ..... The inactive X chromosome in females can be observed microscopically as a densely staining heterochromatic body in the nucleus of some interphase cells. This is called a Barr body."
In different cells of the developing mammalian embryo, it is random which of the two X chromosomes gets inactivated. This leads to a "mosaic" phenotype for sex-linked traits for which a female mammal has a heterozygous genotype. In cats, this is the explanation of the calico phenotype in females heterozygous for the coat-color gene.
2. What do we know about the evolutionary relationship between the human X and Y chromosomes?
From the textbook, (page 305): "Comparative cytogenetic and molecular studies suggest that the X and Y chromosomes began their existence as a pair of ordinary autosomes in the common ancestor of modern mammals and birds. They started to diverge in DNA sequence and gene content at about the same time that the evolutionary lineage of mammals diverged from that of birds, some 300-350 million years ago.
Once SRY (gene that codes for the protein called "testis-determining factor") had evolved as a sex-determining mechansim, the Y chromosome began to diverge in DNA sequence from the X chromosome, and the region of possible X-Y recombination became progressively restricted to the telomeric regions.
This...allows multiple deleterious mutations to accumulate through time because there is no opportunity for recombination to regenerate Y chromosomes that are free of deleterious mutations. Hence, any Y-linked gene whose function is nonessential will tend to degenerate gradually because of the accumulation of mutations."
The lack of recombination along almost the entire length of the Y chromosome makes it possible to trace the inheritance of this chromosome much better than any of the autosomes or the X chromosome. The Y chromosome in any man today is nearly identical to the Y chromosome that his great grandfather had. The term "haplotype" is used to describe a particular set of sequences present in a chromosome. So, we can say that a man has a nearly identical Y chromosome haplotype as his great grandfather.
An amazing example of the use of Y haplotype analysis is shown in Figure 8.11. The red sectors in the figure represent the relative frequency of a group of nearly identical Y chromosome haplotypes. Throughout a large portion of Asia, these account for fully 8% of all men. Based on the base rate of mutation accumulation in the Y chromosome, it can be estimated that the common ancestor lived about one thousand years ago. The presumption is that all of these men are actually descended from Genghis Khan.
3. What can result from "unequal crossing over"?
Figure 8.16 shows how the phenomenon of unequal crossing over can give rise to chromosomes with extra or reduced size (thus a duplication of some genes, or the loss of some genes). This has clear evolutionary implications, because it provides one way in which chromosomes can change and gene "families" can evolve.
A current example of an effect of unequal crossing over is red-green color vision in humans, as shown in Figure 8.17. Near the end of the long arm of the X chromosome, there are two ( or sometimes more) color vision genes that are over 90% similar in DNA sequence. Unequal crossing over (during meiosis in a woman) involving these two loci can result in an egg with an X chromosome that is missing one of the genes or has an extra of one of the genes (fig. 8.17b). Also, one or more of the genes might be "chimeric", if the cross-over occurred in the interior region of the genes. A son resulting from this egg may have some kind of color-blind phenotype.
4. What are "inversions" and "translocations" ?
Textbook page 319: "Another important type of chromosome abnormality is an inversion, a segment of a chromosome in which the order of the genes is the reverse of the normal order." See Figure 8.19.
If a person is heterozygotic for gene order along a given chromosome (i.e., the person is an "inversion heterozygote"), crossing-over in this region during meiosis I can result in abnormal chromosome structures that may prevent viability of the gametes.
Textbook page 322: "A chomosomal aberration resulting from the interchange of parts between non-homologous chromosomes is called a translocation."
If a person is heterozygotic for a translocation (i.e., the person is a "translocation heterozygote"), there will likely be some difficulties in chromosome pairing and segregation in meiosis, probably reducing the person's fertility.