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What is autozygosity mapping?
Autosomal recessive inherited disorders are major causes of developmental and metabolic abnormalities and a wide spectrum of other medical problems, particularly during childhood. An affected individual carries a deleterious mutation in both copies of the responsible gene.
Lander and Botstein pointed out in 1987 that affected children born to consanguineous marriages offer a powerful approach towards disease gene identification. This is because in such families, there is a high probability that an affected individual has inherited both copies (paternal and maternal) of the mutated gene from a common, comparatively recent ancestor.
As a consequence of this principle, the chromosomal region surrounding the mutated gene may be expected to be homozygous; such a chromosomal region is said to be “identical by descent” (IBD) or “autozygous”.
In order to identify disease-causing genes, therefore, homozygous chromosomal segments can be searched for in inbred affected individuals. (This principle is illustrated in the diagram at the bottom of this page.) The localization of disease genes in this way is referred to as “homozygosity mapping” or “autozygosity mapping”.
Autozygosity mapping in Leeds
Autozygosity.org is based within the Leeds Institute of Molecular Medicine and the Leeds and Bradford Teaching Hospitals. The conurbation of Leeds-Bradford and surrounding towns in West Yorkshire has a large population of Pakistani origin, which customarily practices consanguineous marriage. As a consequence, the regional clinical genetics practice deals with an unusual spectrum of recessive inherited disease that result from identity by descent for rare recessive genes.
Work on trying to characterize these genes was begun in 1993 by Bob Mueller, former Director of the Yorkshire Regional Genetics Service, who recognized that the complex consanguinity of local families could be exploited to great effect to identify genes that cause a significant clinical burden.
A series of investigators in Leeds have successfully employed the autozygosity approach to identify causative genes, many of which have proven to have extremely interesting biological properties. The results of our studies have generally translated very rapidly into clinical practice, and mutation analysis for many of these genes has been incorporated into the diagnostic portfolio of the Regional Genetics Service.
Both the University and NHS in Leeds currently receive support to perform autozygosity mapping in local families. The past and future success of our efforts also hinges critically on close collaboration with international colleagues, particularly in Pakistan.
Lander ES, Botstein D (1987) Homozygosity mapping: a way to map human recessive traits with the DNA of inbred children. Science 236:1567-70.
Mueller RF, Bishop DT (1993) Autozygosity mapping, complex consanguinity, and autosomal recessive disorders. J Med Genet 30:798-9.
AutoSNPa is a powerful graphical tool for identification of autozygous regions.