Consanguinity in Centre d'Étude du Polymorphisme Humain (CEPH) pedigrees

Area of Science:

• Human Genetics
• Population Genetics
• Bioinformatics

Background:

• Centre d'Étude du Polymorphisme Humain (CEPH) cell lines are a crucial resource for genetic research, including allele frequency benchmarking, linkage mapping, and gene expression studies.
• These multigenerational families are designed as reference panels with known relatedness, primarily consisting of three-generation pedigrees.

Purpose of the Study:

• To investigate unexpected relatedness and inbreeding within the CEPH cell line collection using identity-by-state (IBS) and identity-by-descent (IBD) methods.
• To benchmark a novel IBD approach (kcoeff) against established software (RELPAIR, PREST).

Main Methods:

• Application of identity-by-state (IBS) and identity-by-descent (IBD) analyses to high-density genotype data from 186 CEPH individuals across 13 families.
• Utilized the kcoeff software for IBD analysis and benchmarked against RELPAIR and PREST.

Main Results:

• Identified significant unexpected relatedness between nominally unrelated grandparents within and between pedigrees, with one pair showing a relatedness coefficient consistent with first-cousins.
• Discovered substantial identity-by-descent (IBD2) values in parent-child and second-degree relationships, alongside regions of homozygosity in offspring indicative of inbreeding.
• Confirmed findings consistent with previous reports of autozygosity in CEPH families.

Conclusions:

• The study reveals previously unrecognized familial relationships and inbreeding within the widely used CEPH reference panels.
• These findings necessitate re-evaluation of interpretations from past studies and careful consideration in the design of future genetic research utilizing CEPH resources.
• The developed kcoeff method provides a reliable tool for assessing relatedness and inbreeding in genetic datasets.