Increased instability leads to the reshuffling of genetic material, creating cut-and-paste alterations — new structural variants — that accelerate the evolution of the human species, said Dr. Aleksandar Milosavljevic, associate professor of molecular and human genetics at BCM and his colleagues. In their research, they report an association between such variation and neuro-cognitive disorders such as schizophrenia, bipolar disorder, autism spectrum disorders and developmental delays in children.
Germline cells are eggs and sperm that, when combined, pass parts of their genetic code in the form of genomic DNA sequences to succeeding generations of organisms. Studying these cells can help determine what influences genetic changes that are passed from one generation to another. This includes single changes in the “spelling of a gene” as well as major structural changes that can duplicate, delete and reshuffle large portions of genomic DNA.
After the genome is established in a developing embryo, other factors come into play, affecting how genes are expressed, what proteins are produced, and how the genome integrity is maintained. One of these changes is called methylation the addition of a methyl molecule to a particular part of the genomic code. Methylation is one of many chemical modifications of genomic DNA and the DNA-bound proteins, collectively referred to as the epigenome. (“Epi” means “on top of” the genome).
The genome changes structurally when it breaks and is repaired by the molecular machinery of the cell. To study how rates of methylation affect genome integrity, Milosavljevic and his colleagues looked at four methylation maps of the human sperm. They also compared these maps with studies that looked for structural variation in the human genome associated with human diseases and in the evolution of the human genome by comparing it to the genomes of chimpanzee and other non-human primates.
The team found that the areas of the genome that are less modified by methylation (methylation deserts) are highly mutable, making them hotspots for evolutionary change as well as a focal point for structural genomic changes associated with neuro-cognitive disorders.
“Schizophrenia has long presented a genetic paradox because twin studies long suggested high heritability (genetic causation of disease), yet genes explaining heritability and high incidence of schizophrenia could not be found,” said Milosavljevic. “The paradox has, in part, been addressed by the recent studies of the genomes of individuals suffering from neuro-cognitive diseases including schizophrenia, bipolar disorder, autism spectrum disorders and developmental delay. It turned out that their genomes have significantly higher chance of carrying rare or de novo (new) structural genomic variants than those of the individuals who do not suffer from these diseases.”
“We have found that these rare and de novo structural variants, as well as changes of the human genome that have accumulated the fastest since the branching chimpanzee are significantly concentrated within methylation deserts,” he said.
“These findings are surprising in two ways,” said Milosavljevic. “First, because mutability decreases individual fitness, it should have been eliminated by natural selection. One way to explain why this has not been the case and why mutability persists in humans is to realize that lack of mutation would stop evolution in its tracks.
“Some amount of mutability may, in fact, be beneficial for the survival of the species. As part of the process, the ‘fittest’ non-mutable individuals and their offspring may be displaced from the population by those carrying the rare successful ‘innovations’. In other words, the double-edged sword of mutability may promote evolutionary innovation while causing disease in almost all individuals affected by mutations. More specifically, our results suggest the high prevalence of neuro-cognitive diseases in humans may in part be explained by the evolutionary trial-and-error required for the rapid evolution of the human brain.”
“The second surprise is that the pattern of structural mutations is marked by hypomethylation of genomic DNA. This is surprising because most evolutionary explanations in the pre-genome era assumed that mutations are essentially randomly distributed throughout the genome. The work of Dr. James R. Lupski, vice chair of molecular and human genetics at BCM, and others led to the realization that some structural mutations are caused by specific genomic sequences. Extending this line of inquiry into causes of genomic instability, we found that hypomethylation, an epigenomic mark, forms a kind of ‘highlight’ on top of the genome, marking an evolutionary ‘work in progress.’ What is in retrospect not so surprising is that these ‘epigenomically highlighted’ genes appear to code for brain development or function.”
The lead author on this paper was Dr. Jian Li, a postdoctoral fellow in Milosavljevic’s laboratory. Others who took part in this research include Drs. R. Alan Harris, Sau Wai Cheung, Cristian Coarfa, Mira Jeong, Margaret A. Goodell, Lisa D. White, Ankita Patel, Sung-Hae Kang, Chad Shaw, A. Craig Chinault and James R. Lupski, all of BCM; Tomasz Gambin of the Warsaw University of Technology; and Dr. Anna Gambin of Warsaw University.
This work was performed as part of the NIH Roadmap Epigenomics Initiative and funded by the National Institutes of Health Common Fund grant (U01DA025956) and an NIH/National Human Genome Research Institute grant (R01 HG004009).