john hawks weblog

paleoanthropology, genetics and evolution

twins

  • Genetics of brain surface area and cortical thickness

    Tue, 2009-12-29 01:02 -- John Hawks

    The field of brain imaging has progressed remarkably during the past several years. I follow the literature because as the study of heritability of brain structure becomes more precise, it may start to be possible to study the polymorphisms that explain the genetic variation of the brain. Twin designs are the most powerful ways of assessing the heritability, although they do present certain weaknesses. A fairly comprehensive recent review of imaging studies of brain structure and heritability in twins is the paper by Peper and colleagues (2007), cited below. Most volumetric measures of the brain and its parts have heritabilities greater than 50 percent; total brain volume is about as heritable as stature in most studies, upward of 85 percent.

    Fifteen years ago, the state of the art was MRI studies of a dozen or so pairs of both monozygotic and dizygotic twins. By the end of the 1990's, studies started to appear that used more than 50 of each type of twin. With sample size, the power of these studies increased. Moreover, advances in imaging technology and software began to allow researchers to focus on smaller structures, first whole lobes, and later smaller parts of the brain.

    Much of your thinking happens in the cerebral cortex, which is a relatively thin layer of tissue, folded around the outside surface of the brain. Lately, MRI studies have begun to explore the structure of the cortex itself, by measuring the surface area of cortex in different regions of the brain, as well as the thickness of the cortex in the same areas.

    Panizzon and colleagues (2009) examined MRIs from the Vietnam Era Twin Study of Aging, numbering 110 monozygotic and 92 dizygotic twin pairs. That sample size makes the study quite powerful for testing heritability, and they find that additive genetic (heritable) factors account for 89 percent of the variation in cortical surface area, and 81 percent of the variation in average cortical thickness. The gray matter volumes of different lobes range from 31 percent to 88 percent additive variance, with unique (non-shared) environmental factors generally accounting for a bit over half the remainder.

    Despite being relatively large compared to most earlier imaging twin studies, the sample of around 200 twin pairs is still relatively weak for testing correlations among brain areas. This limitation is important to keep in mind, because one of the important genetic questions is the extent to which separate developmental modules may be involved in overall brain development. The operation of common factors across different brain regions would be evidence against extreme modularity; independence of different brain measures argues for a modular developmental model.

    After controlling for brain volume, the thickness of the cortex is negatively correlated with surface area in this sample, although non-significantly so. This suggests that these two features of the cortex are relatively independent, instead of being determined by shared factors. That's after controlling for endocranial volume, however, which is strongly positively correlated with surface area. There were very few significant correlations found between different sections of the cortical surface, in either area, thickness, or volume.

    The paper takes the relative independence of cortical area and thickness to be its major finding:

    That surface area and thickness are genetically distinct from one another has numerous implications for continued investigations into the genetic influences of brain structure. Perhaps the most significant of these is the need to explore the genetics of surface area to a greater degree. Like thickness, surface area is a highly heritable construct; yet, it has been largely overlooked in human imaging genetics research. Specific mutations in humans have been linked to excessive gyrification of the cortex as well as an increase in the cortical surface area (Piao et al. 2004; Jansen and Andermann 2005). Animal studies have also demonstrated that manipulation of specific genes can result in dramatic changes in arealization and expansion of select areas of the cerebral cortex like the primary visual area and the primary somatosensory area (Bishop et al. 2000; Mallamaci et al. 2000). Findings such as these would appear to suggest that the genes that influence surface area are critical to the early growth and development of the brain. The observed genetic relationship between total surface area and intracranial volume lends support to this conclusion. If this is the case, then a more focused examination of the genetics of surface area may produce new insights into disorders believed to have early developmental origins, such as schizophrenia (Panizzon et al. 2009: 5-6).

    On one level, these kinds of studies involve incredible technology and massive investment in recruiting and following research subjects. But on another, they are very simple -- measure volumes and areas and plug them into an equation. Total brain volume is among the most heritable gross anatomical measures on the human body, and the lobar divisions of the neocortex are nearly as heritable -- while, interestingly, some smaller parts (such as the hippocampus) are apparently more influenced by unique environmental factors. Surface area and cortical thickness, despite the thin, sheet-like nature of the cortex itself, apparently go along with total brain volume with their relatively high heritabilities.

    References:

    Panizzon MS, Fennema-Notestine C, Eyler LT, Jernigan TL, Prom-Wormley E, Neale M, Jacobson K, Lyons MJ, Grant MD, Franz CE, Xian H, Tsuang M, Fischl B, Seidman L, Dale A, Kremen WS. 2009. Distinct genetic influences on cortical surface area and cortical thickness. Cerebral Cortex (advance) doi:10.1093/cercor/bhp026

    Peper JS, Brouwer RM, Boomsma DI, Kahn RS, Hulshoff Pol HE. 2007. Genetic influences on human brain structure: A review of brain imaging studies in twins. Human Brain Mapping 28:464-473. doi:10.1002/hbm.20398

    Tags: 
    genetics
    twins
    brain
    heritability

  • Searching for the genetics of identical twinning

    Thu, 2009-04-16 14:58 -- John Hawks

    This week, Nature is carrying a news feature by David Cyranoski, which profiles Bruno Reversade, a geneticist trying to find genetic causes of identical twinning in humans. This is not very easy to do, since twinning is rare and sporadic, and does not appear to be heritable in most pedigrees. Still, there are odd cases -- the towns scattered around the world that seem to have too many twin births, or the family that has a lot of cases.

    For example:

    Two years ago he travelled to Jordan to collect saliva samples from members of a family with 15 pairs of monozygotic twins. The family tree fits a pattern in which a dominant gene — one that would cause monozygotic twinning even if only one copy is present — is on one of the 22 autosomal chromosomes. But to make the hereditary pattern work, the gene must have 'variable penetrance', such that some women would not bear monozygotic twins even though they carried a copy of the gene. "Variable penetrance is of course a 'black box'," says Reversade. "Why don't we see more twins?" One reason, he suggests, is that some twins 'vanish' — meaning that at least one of the two dies — during pregnancy.

    Still, there are an awful lot of towns in the world, and an awful lot of families. A single case that produces a lot of twin births is going to happen once in a great while by chance.

    When people find out I have twins, the most common question is "Do they run in your family?" And well, for identical twins it doesn't really matter if you have twins in your family. That's not to say there couldn't be genetic factors, but it does imply that such factors must have a very low penetrance (meaning that twinning is a very unlikely result of carrying an allele). That makes twinning very different from a Mendelian trait, in which the causal alleles have a high penetrance -- for example, all homozygotes for a CF risk allele will develop CF.

    On the topic of the twins "vanishing", the next paragraph contains some astounding numbers:

    According to a widely cited estimate by Charles Boklage, a behavioural and developmental biologist at East Caroline University in Greenville, North Carolina, at least 12% of natural conceptions will produce twin embryos. Both twins come to term in only 2% of those pregnancies. A singleton is born around 12% of the time, and in the vast majority of cases both embryos are lost, often without the pregnancy ever being noticed.

    I don't doubt those -- humans have a very high rate of spontaneous embryonic and fetal losses. Boklage's numbers imply that losses in twin conceptions are a lot higher than otherwise, but both kinds are high compared to most mammals. That's an evolutionary mystery -- why don't we do better carrying conceptions to term?

    After this, the article goes on to discuss some generally questionable evolutionary ideas about twinning in humans. I say "questionable" because the article implies that humans twin "often," calling us "one of the most proficient mammalian species at monozygotic births." The quoted scientists seem to be unaware that monozygotic twinning occurs in chimpanzees at the same frequency as in humans; they also seem oblivious to the fact that dizygotic and monozygotic twinning have similar evolutionary costs and benefits for the mother. Captive chimpanzees have higher dizygotic twinning rates than humans, but neither chimpanzees nor humans are exceptional for primates in their twinning rates.

    Yes, the article ends with a grab-bag of twin stuff, including the story about epigenetic and copy number differences between twins, and that town in Brazil where Mengele supposedly dosed the water with twin-juice.

    Tags: 
    twins
    genetics

  • NY Times: Veterinarian-disguised Mengele brought twins to Brazilian village

    Mon, 2009-02-23 16:09 -- John Hawks

    A reader sent along this NY Times article about the town in Brazil with an unusual concentration of twins. Naturally, it's a Boys from Brazil type of scenario:

    Some researchers have suggested the darker possibility that Josef Mengele, the Nazi physician known as the Angel of Death, was involved. Mengele, residents say, roamed this region of southern Brazil, posing as a veterinarian, in the 1960s, about the time the twins explosion began. In a book published last year, an Argentine journalist, Jorge Camarasa, suggested that Mengele conducted experiments with women here that resulted in the higher rate of twins, many of them with blond hair and light-colored eyes. The experiments, locals said, may have involved new types of drugs and preparations, or even the artificial insemination Mengele claimed to know about, regarding cows and humans.

    But neither Mr. Camarasa nor any other adherent of the Mengele theory has been able to prove the escaped Nazi conducted any experiments here. Mengele, who died in Brazil in 1979, was notorious for his often deadly experiments on twins at Auschwitz, ostensibly in an effort to produce a master Aryan race for Hitler.

    Because everyone knows that's where twins come from. Nazi experiments.

    The most interesting observation is that the unusual number of twins (10 percent of births from 1990-1994) is accompanied by an unusual fraction of identical twins. However, I'd like to see a simple plot showing all similar-sized towns in Brazil. 10 percent of births across a limited time span is not very exciting if we have thousands of towns and pick out the most extreme value.

    Statistics, people. Oh yeah, I suppose the Nazis invented that, too!

    Tags: 
    humor
    twins
    statistics

  • Non-identical identical twins

    Thu, 2008-02-21 08:12 -- John Hawks

    Identical twins may be genetically different due to somatic variations, and a new study by Bruder and colleagues finds that large deletions contribute to some of that difference:

    The exploration of copy-number variation (CNV), notably of somatic cells, is an understudied aspect of genome biology. Any differences in the genetic makeup between twins derived from the same zygote represent an irrefutable example of somatic mosaicism. We studied 19 pairs of monozygotic twins with either concordant or discordant phenotype by using two platforms for genome-wide CNV analyses and showed that CNVs exist within pairs in both groups. These findings have an impact on our views of genotypic and phenotypic diversity in monozygotic twins and suggest that CNV analysis in phenotypically discordant monozygotic twins may provide a powerful tool for identifying disease-predisposition loci. Our results also imply that caution should be exercised when interpreting disease causality of de novo CNVs found in patients based on analysis of a single tissue in routine disease-related DNA diagnostics (Bruder et al. 2008:1).

    If this is a large source of phenotypic discordance between twins -- that is, one twin gets a disease and the other doesn't because of a non-shared somatic CNV -- then our estimates of the heritability of phenotypes based on MZ-DZ twin comparisons will all be too low. This research group is involved in finding genetic risk factors for Parkinson's disease, and they think somatic SNVs are a promising avenue to explain phenotypic discordance where one twin has Parkinson's and the other does not.

    But their study cannot say (because of a lack of power) that phenotypically discordant MZ twins have CNVs that explain the discordance. It's possible that most of the CNVs they observe have no phenotypic effect.

    MZ twins represent an excellent focus for such studies [of somatic CNVs] because any genotypic difference between twins derived from the same zygote highlights an irrefutable case of somatic variation. It is likely that the confirmed CNVs shown here represent only the "tip of an iceberg" of all CNVs that are actually present in the studied twins. The notion of somatic variation being more far more common than previously assumed agrees well with our other, recent results showing CNVs between normal, fully-differentiated tissues within an individual human subject (Bruder et al. 2008:4).

    This does raise an important question. CNVs are a newly-understood component of human genetic variation, for example in the current paper by Jakobsson and colleagues (2008). But if people often exhibit CNV mosaicism, then some of the rare variants in global samples may be somatic mutations that do not occur in the gene pool of their respective populations. And if there are "hotspots" of CNV mutations, then multiple people might show somatic mutations for the same
    variant. It's probably a rare event, but given how little we know about the evolution of CNVs, it might be nice to know how rare.

    References:

    Bruder CEG and 21 others. 2008. Phenotypically concordant and discordant monozygotic twins display different DNA copy-number-variation profiles. Am J Hum Genet 82:1-9. doi:10.1016/j.ajhg.2007.12.011

    Jakobsson M and 23 others. 2008. Genotype, haplotype and copy-number variation in worldwide human populations. Nature 451:998-1003. doi:10.1038/nature06742

    Tags: 
    genomics
    twins
Subscribe to twins

Neandertals

For years, I've worked on their bones. Now I'm working on their genes. Read more about the science studying these ancient people.

Denisova

From a finger bone of an ancient human came the record of a completely unexpected population. My lab is working on the science of the Denisova genome.

Acceleration

The advent of agriculture caused natural selection to speed up greatly in humans. We're uncovering some of the ways that populations have rapidly changed during the last 10,000 years.

Malapa

Just outside Johannesburg, the Malapa site is producing some of the most exciting finds in human evolution. This site is the headquarters of the Malapa Soft Tissue Project.