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Unraveling the Sex-Linked Gene Puzzle

By Dima Abumaria | The Media Line

May 15, 2017

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On the path to personalized treatment and prevention of disease

 

Genes that are mostly active in one sex or the other may play a crucial role in human evolution and health, scientists at Israel’s Weizmann Institute of Science have found.

Several years ago, Prof. Shmuel Pietrokovski and Dr. Moran Gershoni of Weizmann’s Molecular Genetics Department investigated why the prevalence of certain human diseases is common.

Their study found that 15 percent of heterosexual couples are subject to infertility, with a large portion caused by mutations affecting male reproductive genes.

According to the study these gene mutations are found in sperm formation and affect men only and this mutation problem therefore impacts on only half of the population. A mutation that’s detrimental only to half of the population, no matter how damaging, can be freely passed on to the next generation, the researchers found.

“It took us years of analyzing data, studying results and understanding findings to complete the study and publish it,” Pietrokovski told The Media Line.

The research involved advanced computer programs and statistics to analyze the massive amount of data. The gene information used was provided by The Genotype Tissue Expression Project (GTEx). This project was started in conjunction with the US National Institutes of Health in 2010. The goal of GTEx is to learn more about genetically-passed diseases.

The majority of GTEx findings are open for use by researchers and the project offers a tissue biobank and other resources. GTEx has a pool of nearly 550 post-mortem samples of adults whose families consented to have their gene expression measured in various tissues. All GTEx donors were from the US, most were Caucasian; one third were female. Ages ranged between 20 to 79 years old, with two thirds being between 50 and 69.

Close to 20,000 protein-coding genes were analyzed based on sexual characteristics by Pietrokovski and Gershoni while at the same time evaluating the differences in expression for each gene. The researchers found that 6,500 genes expressed differently in men and women.

For example, researchers found gene CALCA, a gene which encodes for peptide hormones, has a biased expression in males, “genetic variations in CALCA was found associated with hypertension; a health condition that is more prevalent in men. It is also known that there is a strong gender component to Alzheimer’s where about 1 in 6 women aged 65 will develop the disease, while only 1 in 11 of men in the same age will” Gershoni told The Media Line.

These findings pave the way to personalized treatment and prevention of disease believes Professor Eitan Friedman, Director of the Oncogenetics Unit at Sheba Medical Center at Tel Hashomer, but, he noted, there is still a lot of work to be done.

“The differences in the genome by gender cannot account for the vast differences seen in real life, in multiple functions, for example body measurements, perception, multi-tasking as well as diseases between men and women,” Friedman told The Media Line.

“It would take a lot more work and functional analyses to decipher what these observed differences in gene expression mean in biology, and even medicine, and before they can be applied to predict or prevent diseases.”

Pietrokovski and Gershoni are still waiting for more data; roughly 1,000 donor samples that will enable them to achieve greater precision in the results, along with expanding the scope of their research to include age, race and other genetic variables.

“The basic genome is nearly the same in all of us, but it is utilized differently across the body and among individuals,” Gershoni pointed out. “Thus, when it comes to the differences between the sexes, we see that evolution often works on the level of gene expression.”

Pietrokovski added: “Paradoxically, sex-linked genes are those in which harmful mutations are more likely to be passed down, including those that impair fertility. From this vantage point, men and women undergo different selection pressures and, at least to some extent, human evolution should be viewed as co-evolution. But the study also emphasizes the need for a better understanding of the differences between men and women in the genes that cause disease or respond to treatments.”

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