Mendelian VS Complex Traits
Genetics is often discussed in terms of the effects of individual genes. Single gene effects are termed “Mendelian” after geneticist Gregor Mendel who famously crossed pea plants to uncover how certain traits are inherited in predictable patterns. Heritable traits like eye color and diseases like cystic fibrosis are dictated by alleles or mutations of single genes.
However, the majority of traits and diseases are “complex”, aka polygenic- meaning that the resulting phenotype (what we see) is influenced by multiple genes. Out of the roughly 20,000 genes in the human genome, only around 4,400 are estimated to produce Mendelian-patterned traits and disorders.
Population Bottlenecks and Founder Effects
In medical genetics, these relatively rare genes are responsible for outsized effects on given diseases, making them appealing (and effective) therapeutic targets. A major challenge is identifying the exact genetic variant responsible for a given Mendelian disorder, particularly if the variant is rare, found in a highly genetically diverse population, or is only harmful when two copies of the variant are present (called a homozygous recessive inheritance pattern).
Some of the most useful resources for identifying clear signals in genome-wide studies are populations with limited genetic diversity. This can happen in populations with recent bottlenecks, producing a founder effect- where a current population is the result of a small pool of initial “founders” either due to catastrophe (like a significant famine) or geographical isolation. The result is a population with low genetic variation and often a much higher incidence of variants that may be rarer in the general population.
FinnGen: Analyzing Finland’s Electronic Health Records
Populations like these are well established in genomics research for GWAS and searching for Mendelian traits. However, to further complicate matters, some genes have monoallelic or biallelic effects- that is to say, one copy of the allele (heterozygosity) produces a different phenotype than two copies of the allele (homozygosity). In a recent Nature paper, Heyne et. al. studied the homozygous and heterozygous effects of 44,370 coding genetic variants on 2,444 disease phenotypes using Finland’s electronic health record data for 176,899 Finnish individuals.
They found that of the 20 recessive disease associations they identified, 13 would have been missed by traditional GWAS methods that don’t account for heterozygous effects, thus indicating many “Mendelian” variants that can’t be explained solely by the dominant and recessive nomenclature normally used. Their study illustrates that large biobank datasets like these, particularly in founder populations, can provide deeper insights into the effects of dosage of Mendelian variants, meaning the number of copies of the variant that are present. The authors found both seemingly benign variants associated with disease effects as well as variants thought to be exclusively recessive that had significant effects when heterozygous as well.
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Jane Cook, Biochemist & Content Writer, Bridge Informatics
Jane Cook, the leading Content Writer for Bridge Informatics, has written over 100 articles on the latest topics and trends for the bioinformatics community. Jane’s broad and deep interdisciplinary molecular biology experience spans developing biochemistry assays to genomics. Prior to joining Bridge, Jane held research assistant roles in biochemistry research labs across a variety of therapeutic areas. While obtaining her B.A. in Biochemistry from Trinity College in Dublin, Ireland, Jane also studied journalism at New York University’s Arthur L. Carter Journalism Institute. As a native Texan, she embraces any challenge that comes her way. Jane hails from Dallas but returns to Ireland any and every chance she gets. If you’re interested in reaching out, please email [email protected] or [email protected].