The primary biological mechanisms responsible for sex-based differences in humans are sex hormones and sex chromosomes (X and Y). However, it is challenging to isolate their individual effects in humans since males typically possess both a Y and an X chromosome (XY) along with male hormone secretion, while females have two X chromosomes (XX) and higher levels of female hormones. Demonstrating the direct influence of sex chromosomes separate from hormones is complex.

A pivotal question in our research is the extent to which sex chromosomes contribute to sex differences at the cellular level.

In a recently published study in Genome Research, we utilized the tendency of cancer cell lines to undergo sex chromosome loss or duplication. We successfully determined the number of sex chromosomes in 355 cancer cell lines from women and 408 from men. The majority of cell lines fell into four categories: normal cells from an XX female and an XY male, cells from a female with one X chromosome lost (X0), cells from a male with the Y chromosome lost (X0).

By using these cell groups, we investigated how sex chromosomes influence gene expression and the essentiality of genes across the genome. In addition to changes in gene expression, we identified genes where mutations had varying effects based on the composition of sex chromosomes in the cells. The most pronounced impact was observed in genes on the X chromosome that had a similar counterpart (paralogous gene) on the Y chromosome. The mutation had a more detrimental effect in cells lacking a Y chromosome. This may be because paralogous genes on the Y chromosome can perform similar functions and compensate for the absence of the gene on the X chromosome.

Furthermore, we conducted a comparison of somatic mutations (mutations occurring in some cells of the body during a lifetime) in an extensive collection of cancer tumors from both men and women. We identified 21 genes on the X chromosome that exhibited a bias in mutation frequency between cancer tumors in men and women. Notably, all these genes had paralogs on the Y chromosome. We also observed that genes with paralogs on the Y chromosome tended to have an increased number of mutations in men but fewer mutations in tumors originating from women. This observation supports the notion that genes on the X chromosome with a paralog on the Y chromosome are more resilient to mutations in males.

Our findings demonstrate that both X and Y chromosomes exert a global influence on gene expression and gene viability. Besides shedding light on the differences between males and females, these results have implications for understanding syndromes involving changes in sex chromosomes and the loss of the Y chromosome, which are frequently observed in cancer cells and during the natural aging process in men.

Read more about this research here:

https://genome.cshlp.org/content/32/11-12/1993.short

 

This phenomenon is observed in various conditions, including degenerative diseases of the central nervous system, vascular diseases, and autoimmune disorders. For example, in autism spectrum disorders, multiple genes related to autism have been identified, but these genes are involved in general biological pathways beyond just the development of the central nervous system.

The specific vulnerabilities of certain tissues in genetic diseases can be explained by several factors. One way to study the effects of gene mutations on specific cell types is through genetic scanning using CRISPR technology. This technology allows for the creation of mutations in specific genes and enables researchers to identify which genes are essential for cell survival.

In our recent study, we analyzed genetic scans that were conducted on 786 different cancer cell lines derived from 24 different tissues. Our study found that most genes essential for a specific tissue are not expressed in higher amounts in that tissue. Therefore, the expression level of a gene cannot solely explain its tissue-specific essentiality. However, it was observed that in tissues unaffected by the mutation, there is often a high expression of homologous genes (genes with a similar protein sequence), which may compensate for the mutation. For instance, the VRK1 gene, associated with developmental damage in the cerebellum, was found to be uniquely essential in nervous system cells. In contrast, the homologous gene VRK2 is expressed in cells from other tissues, potentially explaining why VRK1 is not essential in those tissues. Conversely, there are cases where the presence of a homologue in a cell can make the tissue more vulnerable to mutation due to protein interactions.

Furthermore, the study demonstrated that damage to genes involved in the processing of essential molecules, such as nucleic acids, does not significantly affect cell vitality in most tissues because neighboring cells can supply the missing molecules to impaired cells. However, these genes are essential in blood cells, which do not have the same level of interaction with neighboring cells.

When comparing the findings of the genetic scan to known diseases, it was observed that the genes identified as essential for specific tissues were more frequently associated with various diseases compared to genes essential for all cell types. This suggests that the mechanisms identified, including interactions with homologous genes, are general mechanisms that apply not only to cancer cell lines but also to cells in human tissues.

You can read the full article for more details:

https://academic.oup.com/genetics/article/222/3/iyac134/6692310?login=true

 

Around 1% of children are being diagnosed with autism spectrum disorder that involves social, communication, and behavioral challenges. It is still not clear what type of changes in the brain are responsible for the social difficulties.

Now, a new study led by Reut Suliman-Lavie and Ben Title shows that a mutation in a gene implicated in autism has a pronounced effect on brain development and the function of the cerebellum. The researchers mutated the gene specifically in the brain and found that it affects the social and cognitive behavior in mice in a similar way to what was observed in humans with mutations in this gene. They further showed that this gene regulates the activity of many other genes and is important for the proper activity of brain cells in the cerebellum. The finding, reported in Nature Communications, provides a new understanding of how mutations in a single gene lead to autism. While currently there are no effective drugs to treat autism, this discovery could help finding new ways for developing drugs to treat autism by modulating the neural circuits of the cerebellum.

Read the paper published in Nature Communications

"We recently have been tremendously successful in identifying risk genes for psychiatric disorders by applying new technologies and through extensive collaboration between many scientists. In a way, too successful. The prodigious number of candidate risk genes and the genetic overlap between disorders makes the next step of studying the mechanisms challenging. Newly established detailed gene expression databases, covering brain cell types and different developmental stages, together with systems biology approaches, have been used to explore the convergence between genes and divergence between disorders. The results showed that across disorders, risk genes are likely to be intolerant to mutations and preferentially expressed in the brain. The disorders diverge mainly on the relative contribution of rare vs. common variants, and the timing of expression of the risk genes. Thus, the functional enrichment results are still crude and far from illuminating the neurobiological mechanisms for psychiatric disorders. Perhaps the convergence and divergence will only be found at the neural circuit level." 

Read the paper published in Biological Psychiatry

We performed a genome-wide screen for essential genes in mESCs and compared it to screens in human cells. We found that essential genes are enriched for basic cellular functions, are highly expressed in mESCs, and tend to lack paralog genes. We discovered that genes that are essential specifically in mESCs play a role in pathways associated with their pluripotent state. We show that 29.5% of human genes intolerant to loss-of-function mutations are essential in mouse or human ESCs, and that the human phenotypes most significantly associated with genes essential for ESCs are neurodevelopmental. Our results provide insights into essential genes in the mouse, the pathways which govern pluripotency, and suggest that many genes associated with neurodevelopmental disorders are essential at very early embryonic stages.

Read the paper published in Genome Research

 

A new study, led by Dr. Galya Rothkoff and Prof. Sagiv Shifman, has shown that the AUTS2 gene produces two protein forms - a short and a long version, and the precise expression of these protein forms is essential for regulating neurons generation. During differentiation of embryonic stem cells to neurons a shift from the long to the short protein occurs. 

The two forms of protein display different molecular functions, including which proteins they bind, how they regulate the activity of other genes, and how they affect the process of differentiation to neurons. 

The timing of neuron generation is crucial for determining the size of the brain. This study suggests that microcephaly seen in individuals with mutations in AUTS2 may result from faster differentiation of stem cells to neurons. The study shows that mutations affecting the two forms of the protein lead to a more pronounced cell death during differentiation to neurons.  This observation can explain how the location of mutations can affect severity of symptoms, since the two protein forms are affected by mutations in the end of the AUTS2 gene. 

 Read the paper published in Molecular Psychiatry