Quantification of homozygosity in consanguineous individuals with autosomal recessive disease.
Individuals born of consanguineous union have segments of their genomes that are homozygous as a result of inheriting identical ancestral genomic segments through both parents. One consequence of this is an increased incidence of recessive disease within these sibships. Theoretical calculations predict that 6% (1/16) of the genome of a child of first cousins will be homozygous and that the average homozygous segment will be 20 cM in size. We assessed whether these predictions held true in populations that have preferred consanguineous marriage for many generations. We found that in individuals with a recessive disease whose parents were first cousins, on average, 11% of their genomes were homozygous (n = 38; range 5%-20%), with each individual bearing 20 homozygous segments exceeding 3 cM (n = 38; range of number of homozygous segments 7-32), and that the size of the homozygous segment associated with recessive disease was 26 cM (n = 100; range 5-70 cM). These data imply that prolonged parental inbreeding has led to a background level of homozygosity increased approximately 5% over and above that predicted by simple models of consanguinity. This has important clinical and research implications.
Woods
C Geoffrey
CG
Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom. Electronic address: cw347@cam.ac.uk.
Cox
James
J
Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
Springell
Kelly
K
Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
Hampshire
Daniel J
DJ
Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
Mohamed
Moin D
MD
Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
McKibbin
Martin
M
Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
Stern
Rowena
R
Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
Raymond
F Lucy
FL
Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
Sandford
Richard
R
Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
Malik Sharif
Saghira
S
Department of Clinical Genetics, St James's University Hospital, Leeds, United Kingdom.
Karbani
Gulshan
G
Department of Clinical Genetics, St James's University Hospital, Leeds, United Kingdom.
Ahmed
Mustaq
M
Department of Clinical Genetics, St James's University Hospital, Leeds, United Kingdom.
Bond
Jacquelyn
J
Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
Clayton
David
D
Department of Medical Genetics, Cambridge Institute of Medical Research, University of Cambridge, Cambridge, United Kingdom.
Inglehearn
Chris F
CF
Section of Ophthalmology and Neuroscience, Institute of Molecular Medicine, Epidemiology and Cancer Research, University of Leeds, Leeds, United Kingdom.
D025063:Chromosome Disorders; D003241:Consanguinity; D005532:Foot Deformities, Congenital; D005808:Genes, Recessive; D030342:Genetic Diseases, Inborn; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D010375:Pedigree; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide