A team of researchers from Johns Hopkins has worked for nearly 40 years, searching for the answer to why human sex ratio marginally favored males over females. Well, the findings from a new study may have brought them a little closer to the long sought answer.
Researchers believe they have finally identified a specific part of the human genome that seems to block an RNA that is culpable for keeping only one X chromosome active, when new female embryos are developed, allowing for the normally lethal activation of multiple X chromosomes during the development process. Since the presumed X-inactivation is crucial for natural female embryo development in mammals, including humans and two active X chromosomes generate a genetically fatal condition, the study may assist in explaining the universal human sex ratio that has vaguely favored males over females.
The typical number of chromosomes in a human cell is 46, split into a total of 23 pairs. Twenty-two pairs are autosomes, similar in both females and males. The 23rd pair contains sex chromosomes. For the male gender, an X and Y will be present. Alternatively, the female will consist of two X’s. Researchers have known for a long time that most mammalian females, along with humans have two X chromosomes, but only one is active and most males have one X and one Y chromosome.
Some published studies have identified what influences are behind X-chromosome silencing. The Xist or X-inactive gene is affixed to the X chromosome. During female embryonic development, the Xist produces a protein that extends the length of the chromosome, switching off its genes.
Professor of pediatrics at Johns Hopkins University School of Medicine, Barbara R. Migeon, M.D. said human embryos with triploidy, a chromosomal disorder where three sets of chromosomes are present instead of the normal two, two copies of the X chromosome remained active.
Migeon says the most plausible explanation was a protein that represses the X chromosome silencing activity of X was working overtime, allowing more than one X chromosome to remain activated. However, Migeon has concluded that the gene responsible for this repressor or even its approximate location in the human genome remains been undisclosed.
Identifying the location of the repressor protein and the gene that is responsible for coding it, required intense research. The team of researchers begin by examining cells from human embryos that had varying forms of chromosomal trisomy, a rare disorder in which a portion or all of chromosome 13 appears three times rather than twice. Down syndrome, which is marked by a trisomy of chromosome 21, is only one example.
When two active X chromosomes are present early in development, it can be lethal, which is why the researchers focused on autosomal trisomies.
The research team discovered that every chromosome, except chromosomes 1 or 19, in embryos that survived until later stages contained examples of trisomies. “Trisomies of these chromosomes were missing, suggested that the repressor might be located on one of them,” says Migeon.
The researchers utilized two genetic databases, one developed by Johns Hopkins, the Online Mendelian Inheritance in Man and the other Genome Browser, developed by the University of California, Santa Cruz to examine genomic regions of chromosomes 1 and 19 more closely. These genes are thought to produce proteins that collaborate with Xist.
After searching through different genes that are responsible for subtracting and adding presumed epigenetic marks, which affix to DNA and influence whether a cell can utilize a specific gene. To narrow their search, the researchers turned to yet another database, Decipher, which allowed them to search for genes in the “candidate” regions that displayed distorted sex ratios connected to the quantity of DNA deletions and duplications that could be counted.
The stretch of DNA attached to the short arm of chromosome 19 was the only section of the human genome that fit the criteria. “We now believe that the repressor gene must be located there, because we’ve eliminated all of the other possibilities,” Migeon says.
This region of the genome extends eight megabases and includes all nucleotides that compose the DNA of the human genome. She believes that the gene in this region could possibly unravel the mystery regarding the erratic ratio between genders.
The United States government strictly prohibits almost all taxpayer-funded experiments associated with the human embryo. Certain European governments allow a handful of tests to be conducted within their respective borders. By adding or eliminating excessive copies of genes in the respective region, it may be possible for other scientists to discover the genes that encode Xist’s repressor.
The findings were published in the journal PLOS One in April.