Medical Genetics(2 of 2)

Last week: How did we clone a Mendelian disease gene?

This week: How does a Mendelian disease allele arise?

Tay-Sachs Disease (TSD)

GM2 Gangliosidosis

Bernard Sachs 1887

Konrad Sandhoff1965

Waren Tay1881

• Autosomal recessive degenerative disorder• Mutations affect a gene called HEXA (hexosamidinase) located on CHR 15• Infantile, Juvenile and Adult/Late Onset• First successful genetic screening

Pathophysiology: lipid accumulation

Why is the TSD carrier frequency so high?

Mycobacteriumtuberculosis

1278insTATC allele frequency is 0.0156 among Askenazi Jews

Testing the heterozygote advantage model

No significant differences in mortalitybetween grandparents of carriers vs. non-carriers

Sanger sequencing (old school)

“Jewish Fur Trader Hypothesis”

Founder/Bottleneck Effect