Nature's issue this week released four papers with new insight from the Genome Aggregation Database (gnomAD). Several teams uncovered which genes may be the key to health and ultimately, survival. The root of genetic deficiencies can help medical experts determine how to treat disorders better as scientists discover exactly which genes people can or cannot live without.
This is a lot more complex than it sounds. Gregor Mendel, the 'father of modern genetics' initially conducted heredity studies after observing various traits in pea plants following particular patterns.
The botanist's pea plant analyses generally concluded that traits expressed in 'any species were merely the diluted blending' of present traits in its parents. Further hybrid experiments led to the Law of Segregation, distinguishing which random traits are dominantly or recessively passed on to offspring.
Today, gnomAd is a public resource developed through international collaboration containing '125,748 exome sequences and 15,708 whole-genome sequences from unrelated individuals sequenced as part of various disease-specific and population genetic studies.'
Konrad Karczewski, Laurent Francioli, and Daniel MacArthur wrote the main study, exploring 'genetic variants that inactivate protein-coding genes.' Phenotypic consequences, or traits, of gene disruption, can be derived from this information to determine which variants are needed for healthy functions and which genes can be 'turned-off.'
Genetic Mutation and Parkinson's Disease
Disruptive mutations were introduced into genes to determine effects on physiological and cellular phenotypes on cell lines or mutant organisms. This common approach has uncovered data that became a guide to design therapeutic agents for these mutations. The effect of inactivity which mutations have on genes is not new information, but what the study determined was a new list of mutations causing inactivity without causing harm to genes.
One specific gene they analyzed was the leucine rich repeat kinase 2 (LRRK2 gene), which gives instructions for making dardarin, originally meaning 'to tremble' in Basque. Active in the brain and tissues in the entire body, the protein delivers phosphates to other proteins, including certain cells in the midbrain which produce dopamine. Lack of dopamine leads to Parkinson's disease. After study variants, the study concluded that life-long partial inactivation of this gene is likely to be safe in humans.
Interpretations of other variants led to genes connecting 'their probability of disease impact and other biological properties, and confirm the value of a constraint in prioritizing candidate genes in studies of both rare and common diseases.'
Role of Population Diversity
Karczewski and his team also focused on coding variation, which evaluates 'the strength of natural selection at a gene or region level' in specific populations. Population diversity adds to the complexities of the study with its natural selection implications.
It's important to note that DNA sequence variations wiping out the function of important genes remains rare. Scientists also lack sufficient samples as the data came from European origins. More research can be discovered regarding missing variants and disease risk in other areas.
Investigating gene function and discovering disease genes helped the team conclude that 'genes that are crucial for the function of an organism will be depleted of such variants in natural populations, whereas non-essential genes will tolerate their accumulation.'
