Genetic Variation on Chromosome 6 Influences F Cell Levels in Healthy Individuals of African Descent and HbF Levels in Sickle Cell Patients
Lisa E. Creary1, Pinar Ulug1, Stephan Menzel1, Colin A. McKenzie2, Neil A. Hanchard2, Veronica Taylor3, Martin Farrall4, Terrence E. Forrester2, Swee Lay Thein1,5*
Abstract Top
Fetal haemoglobin (HbF) is a major ameliorating factor in sickle cell disease. We investigated if a quantitative trait locus on chromosome 6q23 was significantly associated with HbF and F cell levels in individuals of African descent. Single nucleotide polymorphisms (SNPs) in a 24-kb intergenic region, 33-kb upstream of the HBS1L gene and 80-kb upstream of the MYB gene, were typed in 177 healthy Afro-Caribbean subjects (AC) of approximately 7% European admixture, 631 healthy Afro-Germans (AG, a group of African and German descendents located in rural Jamaica with about 20% European admixture), 87 West African and Afro-Caribbean individuals with sickle cell anaemia (HbSS), as well as 75 Northern Europeans, which served as a contrasting population. Association with a tag SNP for the locus was detected in all four groups (AC, P = 0.005, AG, P = 0.002, HbSS patients, P = 0.019, Europeans, P = 1.5×10−7). The association signal varied across the interval in the African-descended groups, while it is more uniform in Europeans. The 6q QTL for HbF traits is present in populations of African origin and is also acting in sickle cell anaemia patients. We have started to distinguish effects originating from European and African ancestral populations in our admixed study populations.
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Hi all,
ReplyDeleteThe questions concerning your paper are below. My advice is for you to try to divide them up roughly evenly among your group members. You are even welcome to post the answers independently if you'd like; just be sure to reiterate the questions. Please come see me if you need help!
1. Think back to the QTL paper we discussed in class. What 4-5 general steps do quantitative geneticists take to find a candidate gene for a quantitative trait; and more specifically, what steps did these authors take?
2. The introduction states that the quantity of F cells is under “strict genetic control.” (Incidentally, the heritability of F cell abundance was determined using twin studies (see citation 2)). That said, does VE or VG contribute more to the variance in this phenotype? Draw and/or describe the linear regression scatterplot that would indicate the level of narrow-sense heritability for F cell abundance.
3. The authors discovered three linkage disequilibrium (LD) blocks among their 11 SNPs at the HMIP-2 locus, meaning that the mutant haplotypes in these blocks were found together more often than is expected by their individual frequencies. This locus has a strong influence over the number of F cells in an individual. What might have caused this LD, and what are the implications?
4. The mutant alleles in these linkage blocks lead to an increase in F cells and a corresponding increase in fetal hemoglobin, which is selectively advantageous for in individuals with sickle cell anemia. The second paragraph of the Discussion (page 5) notes that “a large proportion of people with sickle cell disease… have predominantly African ancestry.” Consider your focal disease and explain why this is the case.
Bonus: What’s the functional difference between HbF and adult Hb?
-Dr. Walker