general genetics question

[hoffmann]

why are geneticists so focused on alleles or genotypes as the fundamental unit of genetic variation as opposed to haplotypes? is this too philosophical of a question?

[EthoStrain]

Haplotypes

As I understand it, haplotypes are a way to get a more granular picture of the genotypes of individuals. They were used out of necessity because genotyping was very expensive in the past. By gathering a single genotype on a haplotypes you could know about every other genotype on that haplotype, so in essence you could drastically reduce the necessary read resolution in order to have a deep understanding of an individual person's genotype.

Now we have the HD version of people's genetic code (There are other statistical reasons why haplotypes are extremely useful, but I feel this was a major driver in why they became the gold standard)

[krobison]

Occam's razor would be one component: in most cases we know a single allele drives the actual phenotype. The other variants in the haplotype are neutral bystanders.

However, there are certainly many cases where we know there is really a compound allele -- multiple variants linked in cis create the phenotype. But, even then the haplotype is really too broad a unit -- the biology is being driven by a small number of the variants in the haplotype & the rest is along for the ride. Or at least the observed biology can be mostly explained by a small number.

[Michael.James.Clark]

why are geneticists so focused on alleles or genotypes as the fundamental unit of genetic variation as opposed to haplotypes?

Well, to be frank, it's because they are. A fundamental unit of anything is the original or primary unit, and individual alleles are those fundamental units of genetic variation.

Haplotypes are just collections of alleles that travel together due to close genetic distance, right? Any trait that's traveling with a particular haplotype is doing so because of underlying specific variations (alleles), no? It may be more than one variation, but at the end of the day, it's still specific variations that explain why a given trait is traveling with a haplotype, and those are the things we're interested in.

In short, a haplotype is just a collection of alleles. A "collection" of something cannot be the fundamental unit precisely because it is made up of many units of something else (or, put another way, a collection of fundamental genetic variation units ).

That doesn't mean haplotypes aren't useful in a sequencing world. If we are unable to discern a meaningful variant, we may look at haplotypes as a proxy. As you probably know, this is in fact exactly what we did for many years because we were unable to survey every base in the genome. At the end of the day, however, much of the point of the haplotype was to narrow down a region we could sequence through to find the specific variant responsible for a phenotype. Haplotypes are still useful both for this purpose and for other reasons (tracing ancestry, examining consanguinity, targeted surveying rather than whole genome sequencing, and more).