Re: On Human Diversity From The Scientist
- From: "rmacfarl" <rmacfarl@xxxxxxxxxxxxxxxx>
- Date: 26 Oct 2005 16:39:47 -0700
JAE wrote:
....
> > > admixture linkage disequilibrium
> >
> > Could you please explain what this phrase means Jason?
>
> Briefly, mapping by ALD (ALD mapping or MALD) is a technique whereby
> you look at large blocks of DNA in a population recently formed from
> the mixing of previously long-separated populations. In the new admixed
> population, some individuals will possess traits, others will not
> according to the different DNA that they inherited.
>
> We don't generally have the luxury of first looking and genes and
> figuring out what they do. What usually happens is that we look for
> variation between individuals (e.g. a particular SNP--perhaps
> non-coding) and then see if this variation co-varies with some
> phenotypic variation. If yes, then we can start looking around the SNP
> for candidate genes that got inherited with the possibly neutral SNP,
> then go back and see if the genes similarly co-vary. This is difficult
> though, as recombination shuffles about chromosomes rather quickly such
> that unless the SNP is right next to the gene, something that doesn't
> have to happen, after not too long, recombination will put the SNPs in
> equilibrium with any variation elsewhere and they'll be useless to
> identify any other variation. The solution *may* be to look at more
> markers, but there's no guarantee that there will be this type of
> variation right next to a functional gene.
>
> Imagine this chromosome in a person.
>
> ----------X---------C-----------
>
> where big X is a gene and C is a neutral marker that we've discovered.
> The capital X may cause a disease (or blue eyes or a penchant for being
> really tall, etc.) in this but we didn't find that. We found a C at
> some SNP elsewhere on the chromosome. Little x doesn't cause the
> disease and T is the alternative marker at the other chromosomal
> positions.
>
> e.g.
>
> ----------x---------T-----------
>
>
> Now there are also chromosomes:
>
> ----------X---------T----------- (the disease, but different
> associated marker)
>
> and
>
> ----------x---------C-----------
>
> all of which can be generated by recombination. After not too long,
> all of them do exist and as such, the X-x polymorphism (our unknown) is
> in equilibrium with the T-C polymorphism and one isn't useful for
> identifying the other. We won't find any co-variation to help us
> narrow down the search for X.
>
> We can look at a whole lot more markers and hope that there's something
> like this,
>
> ----------X-G-------C/T-----------
>
> Where the G is so close to our gene that recombination shuffles it less
> often, but that's rarer and even so, eventually, recombination will
> break this up too. It just takes longer, but it will happen.
>
> MALD is one way of getting around this problem. The admixed population
> will have a subset of the variability and early on, recombination won't
> be as big a deal. In a recently admixed population, the chromosomal
> blocks haven't undergone as much recombination and as such, markers
> farther away may still be linked to genes. A natural bottleneck
> filters out only part of the neutral variation and it's early on linked
> to the polymorphic gene-state of interest.
>
> We hope that in this population, we just got the
>
> ----------X---------C-----------
> type from one population and before recombination we'll get one or the
> other chromsome block in people and have clearer association between
> the variability we've found and the disease.
>
> MALD looks at several sites on several chromosomes (several 100 to
> several 1000s) and looks for association rather than looking at
> millions of sites. It's just a way of improving the odds. It's a very
> useful technique. It doesn't always work, but it's helpful in many
> instances.
>
> [Looking back, I don't think I explained that very well, but I hope
> it's a start.]
>
> > > as a means to start addressing some of
> > > this variation, but on the success stories, falls back on genes
> > > identified with hypertension rather than some other non-disease aspect
> > > of biological variation.
> >
> > I wonder if that's because there is more data available on genes that
> > are linked to disease, especially one as common as hypertension?
>
> More data is available because diseases get charted when people get
> treatment. There's also more discrete diseases (e.g. you have it or you
> don't) rather than more continuous traits like height. More funding is
> available for looking at this too. All are important.
When I started getting interested in PA I read a book called The Human
Blueprint, by Robert Shapiro. I remember the chapter on Huntington's
chorea especially, because a few years later we had friends whose son
was diagnosed with it. He died at the age of 7, which was tragic, and
unusual, because it's caused by a dominant gene that normally strikes
adults in their 30s and 40s, after they've reached child-bearing age.
So when I found out his diagnosis, I immediately knew it would afflict
his father as well.
Shapiro, Robert, The Human Blueprint, New York: St. Martin's Press,
1991...
Ross Macfarlane
.
- References:
- Re: On Human Diversity From The Scientist
- From: JAE
- Re: On Human Diversity From The Scientist
- From: rmacfarl
- Re: On Human Diversity From The Scientist
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