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--- chapter_21 [2024/09/18 19:37] – [Simple sequence repeats (SSRs)] mike
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+<- chapter_20|Chapter 20^table_of_contents|Table of Contents^chapter_22|Chapter 22 ->
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 In 2002, a team of Finnish scientists set out to use human genetics methods to identify mutations that are associated with hypolactasia. They reasoned that mutations that affect individuals are probably not in the protein-coding region of $LCT$, since these individuals could digest lactose as children (they also knew from other studies that there were no mutations in the $LCT$ gene of individuals that had hypolactasia). Instead, they believed that there may be mutations in nearby cis-acting regulatory sequences (see [[chapter_13|Chap. 13]]) that control the expression of $LCT$, such that it is no longer expressed in adults (they also had some other evidence to support this idea).
-The scientists examined the pedigrees of nine Finnish families with a history of hypolactasia (Fig xxx: NOTE: WAITING FOR PERMISSION FROM HHMI TO USE THE FIGURES). From the pedigrees, you can see that the inheritance pattern is consistent with hypolactasia being an autosomal recessive mutation. The scientists then collected DNA samples from volunteers in these families and analyzed various polymorphisms. They utilized seven SSRs that flanked the $LCT$ gene on either side. They found strong statistical evidence (see [[chapter_22|Chap. 22]]) for linkage of hypolactasia to an SSR upstream of the $LCT$ gene - consistent with it being a regulatory mutant instead of a coding mutant. They then used SNPs to further narrow down the genetic interval for the mutations to a 47 kb region of DNA upstream of $LCT$. In this region, they found many DNA polymorphisms among the family members, but only two SNPs that showed complete co-segregation with the hypolactasia trait. Subsequent reverse genetic studies in mice and cultured human cells suggest that these two SNPs may be mutations that affect the ability of a transcription factor called OCT-1 to bind, thereby affecting the expression of $LCT$ in adults.
+The scientists examined the pedigrees of nine Finnish families with a history of hypolactasia (Fig xxx: NOTE: WAITING FOR PERMISSION FROM HHMI TO USE THE FIGURES). From the pedigrees, you can see that the inheritance pattern is consistent with hypolactasia being an autosomal recessive mutation. The scientists then collected DNA samples from volunteers in these families and analyzed various polymorphisms. They utilized seven SSRs that flanked the $LCT$ gene on either side. They found strong statistical evidence (see [[chapter_22|Chap. 22]]) for linkage of hypolactasia to an SSR upstream of the $LCT$ gene - consistent with it being a regulatory mutant instead of a coding mutant. Since SNPs are much denser than SSRs, they then used SNPs to further narrow down the genetic interval for the mutations to a 47 kb region of DNA upstream of $LCT$. In this region, they found many DNA polymorphisms among the family members, but only two SNPs that showed complete co-segregation with the hypolactasia trait. Subsequent reverse genetic studies in mice and cultured human cells suggest that these two SNPs may be mutations that affect the ability of a transcription factor called OCT-1 to bind, thereby affecting the expression of $LCT$ in adults.