posted on 2016-11-25, 14:00authored byA. Mesut Erzurumluoglu, H. A. Shihab, S. Rodriguez, T. R. Gaunt, I. N. Day
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.
Funding
Mesut Erzurumluoglu is a PhD student funded by the Medical Research Council (MRC UK). This work was supported by the Medical Research Council (MC_UU_12013/8 and G1000427).
History
Citation
Annals of Human Genetics, 2016, 80 (3), pp. 187-196
Author affiliation
/Organisation/COLLEGE OF MEDICINE, BIOLOGICAL SCIENCES AND PSYCHOLOGY/School of Medicine/Department of Health Sciences
Additional Supporting Information may be found in the online
version of this article:
Table S1: Potential LoF Mutations in the Human Genome.
Figure S1: Comparison between offspring of outbred individuals
and first cousins using the example of an allele for
which q = 0.1 (frequency of 1 in 10 in a population) and
there are three unrelated homozygotes (i.e., AA) who marry
into the family.
Figure S2: Comparison between offspring of outbred individuals
and first cousins using the example of an allele for
which q = 0.001 (frequency of 1 in thousand in a population).
Figure S3: Example of a complex pedigree with multiple
consanguineous unions.
Figure S4: Factors influenced by consanguineous unions
and/or by living in a highly consanguineous region.
Figure S5: Autozygosity mapping and consanguinity.