Razib Khan One-stop-shopping for all of my content

December 29, 2011

How a “designer baby” might just work

Filed under: Bioethics,Quantitative Genetics,Quantitative Genomics — Razib Khan @ 1:41 pm

In earlier discussions I’ve been skeptical of the idea of “designer babies” for many traits which we may find of interest in terms of selection. For example, intelligence and height. Why? Because variation on these traits seems highly polygenic and widely distributed across the genome. Unlike cystic fibrosis (Mendelian recessive) or blue eye color (quasi-Mendelian recessive) you can’t just focus on one genomic region and then make a prediction about phenotype with a high degree of certainty. Rather, you need to know thousands and thousands of genetic variants, and we just don’t know them.

But I just realized one way that genomics might make it a little easier even without this specific information.

The method relies on the phenotypic correlation between relatives. Even before genomics, and genetics, biometricians could generate rough & ready predictions about phenotypic values based on parental values. The extent of the predictive power depends upon the heritability of the trait. A trait like height is ~80-90% heritable. That means that ~80-90% of the variation in the population of the trait is due to genes. The expected value of your height is strongly conditional upon the heights of your parents.

That’s all common sense. What does this have to do with genomics? Simple. You are 50% identical by descent with each parent. That means half your gene copies come from your mother and half from your father. You can’t change that unless you’re a clone. But, because of the law of segregation and recombination you are not necessarily 25% identical by descent from each grandparent! The expectation is that you’re coefficient of relatedness is 25%, but there is variation around this. A given parent either contributes their own paternal or maternal homologous chromosome. There’s a 50% chance that you’re going to inherit one or the other across your chromosomes, of independent probability. You have 22 autosomal chromosome pairs (non-sex chromosomes), so there’s a strong chance that you won’t be equally balanced between your opposite sex paternal and maternal grandparents (e.g., you have more genes identical by descent from your paternal grandfather than paternal grandmother).* Second, recombination is also going to generate new combinations. In the generation we’re concerned about this will work against the dynamic we’re relying on, by swapping segments across homologous chromosomes from the parents’ mother or father.

The ultimate logic here is to select for zygotes or gametes which are biased toward the grandparents with phenotypic values which you are interested in. To give a concrete example, if you have a parent who is moderately tall, whose own father was very tall, while the mother was somewhat short, and you want the tallest possible child, you’ll want to select zygotes with the most gene content identical by descent with the tall grandparent. The point isn’t to pick specific genetic variants, you don’t need to know that. All you know is that the tall grandfather probably had genes which resulted in a predisposition toward being tall. So just make sure that the grandchild has as much of that grandparent “in them.”

I still don’t know if this is going to be cost effective in the near term. But I began to think of it because in the near future I’ll be checking the genotype of a child who has a full pedigree of 1,000,000 SNPs of their parents and grandparents.

* Modeling it as a binomial, about 1 in 7 cases will have the expected 11 chromosomes from a focal grandparent. The standard deviation is more than 2 chromosomes. You need to have about 100 zygotes to expect to get any individuals who are 5 chromosomal units away from the expected value (i.e., the individual is 10-15% instead of 25% one grandparent, or 35-40%). Obviously you need more to be assured of getting zygotes of that value. And I neglected recombination, which would work against this, by swapping genomic regions….

August 10, 2011

Half the variation in I.Q. due to variation in genes

A new paper in Molecular Psychiatry has been reported on extensively in the media, and readers have mentioned it several times in the comments. I read it. It’s titled Genome-wide association studies establish that human intelligence is highly heritable and polygenic. But the fact is that I read this paper last year. Back then it was titled Common SNPs explain a large proportion of the heritability for human height. I kid, but you get the picture. The new paper establishes for intelligence what we already suspected: most of the genetic variation in this heritable trait is accounted for by numerous genes of small effect. You inherit variants of these numerous genes from your two parents, and your own trait value is to a large extent a combination of the parental values. The issue is not if intelligence is heritable, but the extent of that heritability.

The standard way to estimate human heritability was to track similarities across individuals with varying degrees of relatedness. For example, compare identical twin correlations on a trait with fraternal twin correlations. The main objection to these methods is that one could argue ...

February 3, 2011

Why siblings differ differently

The Pith: In this post I examine how looking at genomic data can clarify exactly how closely related siblings really are, instead of just assuming that they’re about 50% similar. I contrast this randomness among siblings to the hard & fast deterministic nature of of parent-child inheritance. Additionally, I detail how the idealized spare concepts of genetics from 100 years ago are modified by what we now know about how genes are physically organized, and, reorganized. Finally, I explain how this clarification allows us to potentially understand with greater precision the nature of inheritance of complex traits which vary within families, and across the whole population.

Humans are diploid organisms. We have two copies of each gene, inherited from each parent (the exception here is for males, who have only one X chromosome inherited from the mother, and lack many compensatory genes on the Y chromosome inherited from the father). Our own parents have two copies of each gene, one inherited from each of their parents. Therefore, one can model a grandchild from two pairs of grandparents as a mosaic of the genes of the four ancestral grandparents. But, the relationship between ...

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