Linkage analysis and the study of Mendelian disease in the era of whole exome and genome sequencing


Whole exome and whole genome sequencing are now routinely used in the study of inherited disease, and some of their major successes have been the identification of genes involved in disease predisposition in pedigrees where disease seems to follow Mendelian inheritance patterns. These successes include scenarios where only a single individual was sequenced and raise the question whether linkage analysis has become superfluous. Linkage analysis requires genome-wide genotyping on family-based data, and traditionally the linkage analysis was performed before the targeting sequencing stage. However, methods are emerging that seek to exploit the capability of linkage analysis to integrate data both across individuals and across pedigrees. This ability has been exploited to select samples used for sequencing studies and to identify among the variants uncovered by sequencing those mapping to regions likely to contain the gene of interest and, more generally, to improve variant detection. So, although the formal isolated linkage analysis stage is less commonly seen, when uncovering the genetic basis of Mendelian disease, methods relying heavily on genetic linkage analysis principles are being integrated directly into the whole mapping process ranging from sample selection to variant calling and filtering.

Briefings in Functional Genomics 2014; 13(5):378-383