NEW YORK (GenomeWeb) – A major European Huntington's disease haplotype has ancient roots, according to a sequence-level investigation.
Huntington's disease is a dominantly inherited neurodegenerative disorder marked by an extended CAG trinucleotide repeat expansion in the coding sequence of the huntingtin gene HTT, and recent work has found that there are seven common haplotypes associated with Huntington's disease in Europeans.
Researchers from Massachusetts General Hospital and elsewhere performed whole-genome sequencing on members from four families harboring the hap.01 Huntington's disease haplotype that's found in about half of European-ancestry families with the disease. As they reported in the American Journal of Human Genetics today, the researchers found that these four families share a common ancestor, though that ancestor likely did not have Huntington's disease.
"Our sequence-level analysis of the major HD-associated HTT haplotype supports the previous hypothesis from HD haplotypes that multiple different origins of the CAG-expansion mutation have contributed to the European HD population," Mass General's James Gusella and his colleagues wrote in their paper.
The researchers' analysis also unearthed heterozygosity within patients that they said could aid in the development of allele-specific gene-targeting therapies for Huntington's disease.
Gusella and his colleagues sequenced the whole genomes of 38 people from four HD-affected families in which hap.01 segregates with disease. Their analysis included 29 people with expanded HTT CAG repeats and nine normal relatives.
They further phased the haplotypes using father-mother-child trios, drawing on 16 trios from the four families, to reveal family-specific haplotypes.
These family-specific haplotypes, the researchers noted, were nearly identical, suggesting a common ancestral origin.
Using the bases confidently phased in all four families, they reconstituted the shared founder haplotype. The founder haplotype differed from the human reference genome at 27 bases, including the delta2642 deletion allele that marks the hap.01 haplotype in HD families.
Although the family-specific haplotypes mostly jibed with the consensus ancestral haplotype at most sites, the researchers noted that they diverged at seven variant sites.
The accumulation of such family-specific variants within an otherwise identical haplotype indicates it has an ancient origin, Gusella and his colleagues said. Indeed, by sifting through recently reported genome-wide SNP data, they uncovered a haplotype identical to hap.01 in an individual belonging to a 5,700-year-old Swedish Mesolithic culture.
In most disorders linked to a founder haplotype, the ancient common ancestor had the disease-causing mutation, but here the researchers said the common ancestor most likely did not have an expanded CAG repeat. They noted that some families with a delta2642 deletion allele on chromosomes with either hap.01 or hap.05 have undergone de novo expansion of the HD-producing CAG allele, indicating that a disease haplotype can be traced back to a progenitor without disease.
One area of interest for treating HD is sequence-based silencing of the mutant allele, the researchers said. To do so, they added, the disease haplotype would need to be distinguishable from the patient's normal HTT haplotype. In European patients with HD, the two most common haplotypes are hap.01 and hap.08, which is the most frequent haplotype in the normal European population.
By comparing these two haplotypes in their study population, the researchers reported 109 differences between them, presenting potential targets for allele-specific gene silencing.
However, this diplotype only accounts for just more than 10 percent of European HD individuals, suggesting to Gusella and his colleagues that a personalized approach might be needed to offer this strategy to the HD population at large.