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Angela
16-09-15, 16:26
I couldn't fit it; it should say Finns and Indians. The paper on Indians has members of the Reich Lab as authors.

Young Northern Finnish founder population reveals enrichment of rare recessive and dominant gene variants in neurodevelopmental disorders.

Authors:
M. I. Kurki1,2 ; O. Pietiläinen3 ; E. Saarentaus4 ; E. Hämäläinen4 ; J. S. Moilanen5 ; O. Kuismin5 ; M. Daly6 ; A. Palotie1,2,4 ; Sequencing Initiative Suomi consortium


Institutes
1) Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA; 2) Stanley Center, Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA; 3) Department of Stem Cell and Regenerative Biology, University of Harvard, Cambridge, Massachusetts, USA; 4) Institute for Molecular Medicine Finland (FIMM), University of Helsinki, Helsinki, Finland; 5) Department of Clinical Genetics, Oulu University Hospital, Medical Research Center Oulu and PEDEGO Research Group, University of Oulu, Oulu, Finland; 6) Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, Massachusetts, USA.
"Abstract:
Genetic variants with strong reproductive disadvantages are evolutionary constrained and remain generally rare in population. However, these variants can still exist at higher frequencies in young populations, such as Finns, when the negative selection hasn’t had time to counteract the effect of genetic drift on rare alleles. Thus, population isolates provide a valuable study design to explore the role of rare genetic variants in complex traits. In Finland, the youngest settlement is in the north and east parts of the country dating back to a small number of founder families only few centuries ago. In addition this region has higher prevalence of schizophrenia and intellectual disability (ID). We exploited this hypothesis by producing whole exome sequence (WES) and GWAS data from 352 patients from Northern Finland with ICD-10 diagnosis of ID of unknown etiology, and their 293 family members (97 trios, 109 duos and 146 index cases). The Northern Finland Intellectual Disability Project (NFID) exomes were combined with 8000 Finnish exomes sequenced in the Sequencing Intitative Suomi project (SISu, http://sisuproject.fi/).As (http://sisuproject.fi/%29.As) expected, we observed comparable amount of large CNVs and de novo mutations as reported in similar patient collections, both of these categories being enriched in the NFID patients. Given the genetic origin of NFID, we expected to observe variants enriched in Finland that are 1) strong acting recessive variants that seem Mendelian but account for ~1% of a 1% phenotype rather than all of a 1/10000 phenotype and 2) dominant alleles with odds ratios in the range of 2-5.As per our hypothesis we discovered a Finnish-specific recessive cause of ID in 4 cases, homozygosity of a variant in CRADD (p=4e-8). The variant is not observed in homozygous state in 61 000 individuals worldwide (http://exac.broadinstitute.org/) (http://exac.broadinstitute.org/%29) or in 8000 Finnish individuals. We also observed Finnish enriched dominant missense variants in multiple genes (OR range 3-6) including a gene encoding for TUBA1A1 (OR 5.2, p:4e-8). Significant and promising variants are replicated by sequencing additional Northern Finnish ID cases and their family members (n=315; 150 cases; 51 trios).In conclusion, we demonstrate young founder populations as a powerful resource to study rare variants. Specifically, we show that an enrichment of deleterious alleles increases power to detect causal and disease associated variants that would require very large sample sizes in more diverse populations."

I think this has broader implications in terms of population genetics in general.

Isn't it the luck of the draw when you're talking about results like this from founder effect and drift, however? If the few founder families don't carry the genes for ID and Schizophrenia they can't rise in frequency due to drift.


"Recessive disease gene mapping in India: extraordinary opportunities for understanding health and disease.

Authors:
N. J. Nakatsuka1 ; K. Thangaraj2 ; P. Moorjani1,3,4 ; A. Tandon1,3 ; N. Patterson3; L. Singh2 ; D. Reich1,3,5


Institutes
1) Department of Genetics, Harvard Medical School, Boston, MA USA; 2) Centre for Cellular and Molecular Biology, Hyderabad, India; 3) Broad Institute of MIT and Harvard, Cambridge, MA USA; 4) Department of Biological Sciences, Columbia University, New York, NY USA; 5) Howard Hughes Medical Institute, Harvard Medical School, Boston, MA USA.
Abstract:
Modern India is a region of remarkable cultural, linguistic, and genetic diversity with over 4,500 anthropologically well-defined groups. Large genetic differentiation has been observed between many of these groups, reflecting strong founder events with effects that have been preserved in some cases for thousands of years due to low genetic exchange between groups. We undertook a systematic survey to assess the strength of founder events in over 1200 individuals from over 230 Indian groups genotyped on Affymetrix (6.0 and Human Origins) and Illumina (650K) arrays. These groups include tribes, castes, and religious groups with a wide-range of census sizes and spanned every state in India. We also analyzed Ashkenazi Jews and Finns, two groups known to have high rates of recessive diseases due to strong founder events. To determine the severity of founder events, we measured the total length of the genome inherited identical-by-descent (IBD) in each group. The data were phased with Beagle 3.3.2, and detection of IBD fragments was performed using FastIBD and GERMLINE. The HaploScore algorithm was used to filter out false positive fragments. To reduce the influence of recent consanguinity, we excluded closely related individuals detected by the presence of very long IBD segments. We quantified the IBD score for a group as the combined length of IBD segments between 3 to 20cM long, averaged over all pairwise comparisons within the group. We find that over 100 Indian groups in our dataset have founder effects stronger than in Ashkenazi Jews and Finns, including many groups with large census sizes (>1 million). This represents an extraordinary opportunity for biological discovery and potential reduction of genetic disease burden through mapping of recessive disease genes and prenatal counseling. Future work should focus on better characterization of the history and relationships amongst the founder events, as well as mapping variants associated with genetic diseases in the groups with the strongest founder events."

For me, the moral of the story is that there are big dangers in marrying only "your own kind". Genetic diversity is good. Even large population sizes aren't enough to counteract the dangers of inbreeding.

Tomenable
16-09-15, 19:24
For me, the moral of the story is that there are big dangers in marrying only "your own kind". Genetic diversity is good. Even large population sizes aren't enough to counteract the dangers of inbreeding.

Mixed individuals have lower levels of homozygosity: https://www.youtube.com/watch?v=zR57HDOdEEQ#t=181

Do you know from which documentary is this fragment in the video above? I can't find the original film...

Angela
16-09-15, 22:48
Mixed individuals have lower levels of homozygosity: https://www.youtube.com/watch?v=zR57HDOdEEQ#t=181

Do you know from which documentary is this fragment in the video above? I can't find the original film...

Sorry, I don't.

I would bet that different parts of Europe have different levels of homozygosity, however, i.e. Italians having less homozygosity than, say, a lot of northern and eastern Europeans.

Wasn't there a paper out recently saying that one Scandinavian group descended from a very small founding population?

I try to keep that in mind when looking at modern results compared to ancient ones. It can be very random who actually survives, so who knows how accurate our predictions about the interactions of ancient groups really are in the final analysis?

Although, it would depend whether you were testing an urban person versus someone like my father and his family: 500 years living in the same dozen or so villages stuck on the top of the northwestern Apennines has got to result in a lot of homozygosity. No big genetic load, though, and Cavalli-Sforza was looking for it. They never found a big cluster of recessive (or dominant allele) genetic diseases up there.

Like I said, it's the luck of the draw. If they every colonize other parts of the universe, they better check the genetic fitness of the colonizers. :)

I was surprised at the statement below, and wouldn't the Indian woman's results in the video contradict this?

"We find that over 100 Indian groups in our dataset have founder effects stronger than in Ashkenazi Jews and Finns, including many groups with large census sizes (>1 million)"