Jones, B.L.; (2012) Lactase enhancer diversity and adaptation for the lactase persistence trait in East African pastoralists. Doctoral thesis, UCL (University College London).
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The persistence of lactase into adult life in some humans is a genetic trait that is considered to have been under strong directional positive selection, with the ongoing expression of lactase due to cis-acting mutations in an upstream enhancer region that disrupt transcription factor binding. In Europe this is reflected by the high frequency of a single regulatory mutation that lies on an extended haplotype. In Africa, and the Middle East however, the European allele is infrequent although several other mutations have since been identified that show association with, and/or functionality, with respect to the lactase persistence trait. These mutations are clustered in the same enhancer element that is known to have several transcription factor binding sites. These variants occur on different haplotypic backgrounds indicating that they cannot be markers of a common causal element but that the persistence of lactase has evolved in parallel more than once. Whilst virtually absent in non-digesters, several of these functional alleles can be found in a single ethnic group displaying the signature of a soft selective sweep. In contrast to a hard selective sweep, where a single beneficial mutation under selection rises in frequency and is found on an extended haplotype, a soft selective sweep describes the situation where several alleles that result in the same beneficial phenotype simultaneously rise in frequency, typically maintaining haplotypic diversity. These beneficial alleles may have arisen from standing variation (where previously the allele may have been neutral or mildly deleterious), new mutation, or the migration of alleles. Soft selective sweeps have, to date, not been well characterised in the human population. This thesis investigates genetic diversity across the lactase enhancer region, and two flanking regions approximately 16kb upstream and 14kb downstream of the enhancer. DNA from an Ethiopian cohort of 386 lactose tolerance tested individuals was used to search for previously undiscovered, or unconfirmed, genetic variation that may be causal of lactase persistence, and we attempt to refine the sequence region that is likely to have been important in the evolution of this adaptive trait. In conjunction with these data, and to consider the different modes of selection active in different populations in relation to this phenotype, we sequenced the lactase enhancer and the two flanking regions in 25 population groups from across Africa.
|Title:||Lactase enhancer diversity and adaptation for the lactase persistence trait in East African pastoralists|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment|
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