Importance of Genetic Studies in Consanguineous Populations for the Characterization of Novel Human Gene Functions

Abstract

Consanguineous offspring have elevated levels of homozygosity. Autozygous stretches within their genome are likely to harbour loss of function (LoF) mutations which will lead to complete inactivation or dysfunction of genes. Studying consanguineous offspring with clinical phenotypes has been very useful for identifying disease causal mutations. However, at present, most of the genes in the human genome have no disorder associated with them or have unknown function. This is presumably mostly due to the fact that homozygous LoF variants are not observed in outbred populations which are the main focus of large sequencing projects. However, another reason may be that many genes in the genome-even when completely "knocked out," do not cause a distinct or defined phenotype. Here, we discuss the benefits and implications of studying consanguineous populations, as opposed to the traditional approach of analysing a subset of consanguineous families or individuals with disease. We suggest that studying consanguineous populations "as a whole" can speed up the characterisation of novel gene functions as well as indicating nonessential genes and/or regions in the human genome. We also suggest designing a single nucleotide variant (SNV) array to make the process more efficient.

Keywords: Consanguineous populations; Mendelian disease; autozygosity; complex disease; gene function.

Figure 1

Examples of inferences to be gained from autozygous regions in consanguineous offspring. (a) Homozygous LoF mutations in gene 1 causes ARID, (b) Gene 2 is likely to be a nonessential gene (i.e., dispensable). The subject should be followed up for late‐onset effects or via deeper phenotyping. (c) Although gene 3 can cause primary ciliary dyskinesia (PCD), the coding region from the stop gain to the end of the exon is not essential for correct functioning of the gene, hence the unaffected subject (NB: mutation is not a target for NMD). (d) Although LoF mutations in gene 1 cause ARID, concurrent inactivation of gene 21000 (arbitrarily chosen number) due to NMD masks disease phenotypes indicating interaction between the two genes products in the causal pathway (e.g., gain of function mutation at gene 1 could become dysfunctional by mutation at gene 21000). X: Stop gain. Ø: Deletion/inactivation of whole gene. Position of stop gain within genes is for illustration purposes. This is not an exhaustive list of all the possible inferences which could be gained from studying consanguineous populations (e.g., identifying dispensable regions, proxy molecular diagnoses (see Erzurumluoglu et al. 2015b for details on the latter).

Figure 2

Example of difference between union of (a) unrelated and (b) related individuals. Although everyone possesses rare LoF mutations within their genome, they are likely to be unique to their family (or themselves). Therefore, the offspring of unrelated individuals have an almost zero probability of being homozygous for these variants. Since related individuals will have a fairly recent common ancestor, their ancestors’ LoF mutations will be passed on and there is on average a 6.25% chance of these mutations to be in a homozygous (or more correctly, autozygous) state in the offspring of first cousins. Thick black lines represent LoF mutations. The figure has been simplified for clarity (e.g., does not include recombination events).