Tag Archives: inbreeding

Ashkenazi Jews are extremely inbred

Neurologists are inherently interested in  psychosis, not least because too much dopamine in the form of L-DOPA can trigger it.  I’ve always found it remarkable that dopamine blocking agents (phenothiazines, and most antipsychotics) can attack psychotic thought itself.  This is much more impressive to me than the ability of other drugs (alcohol, coffee, marijuana, cocaine) to affect mood.

So it’s always worthwhile to read another paper about the genetics of schizophrenia, a very hereditary disease.  All the risk factors we’ve found by GWAS (Genome Wide Association Studies) account for at most of 1/3 of genetic risk in schizophrenia.  For details please see https://luysii.wordpress.com/2014/08/24/tolstoy-rides-again-schizophrenia/.

So I was interested in another crack at finding more genetic causes of schizophrenia  [ Neuron 109, 1465–1478, May 5, 2021 ].  As often happens, the most interesting thing in the paper was something totally tangential  to my original interest in it. 

Here it is —   ”  For example, the Ashkenazi Jewish (AJ) population, currently numbering >10 million individuals world- wide, effectively derives from a mere 300 founders 750 years ago ” (Carmi et al., 2014;Nat. Commun. volume 5, 4835.).  

I find this assertion incredible.  But, as explained below, there is pretty good evidence (although subtle and quite technical) that it’s correct.

Ashkenazi Jews are those previously found only in Europe and the Americas, as opposed to Sephardic Jews, previously found only in the mideast and Africa.  Both are now found in Israel.  Ashkenazi Jews were chosen for the study because any deleterious genes producing schizophrenia  present in the original 300 wouldn’t have been washed out by natural selection in just 30 generations in 750 years. 

The Ashkenazim make the inbreeding among French Canadians look like pikers — a population of 2 million derived from a founder population of 9000 people over the next 170 years — for details please see https://luysii.wordpress.com/2019/07/17/the-wages-of-inbreeding/.  Note that neither population tried to inbreed, it’s just that there was no one else geographically available to breed with for the French Canadians, and no one else culturally available for the Ashkenazi’s.  

At least with the French Canadians we have immigration records to tell us how large the founder population was.  How sure are we about the 300 strong founder population of present day Ashkenazi Jews?  We’re not and I’m not even though it was published in a peer reviewed reputable journal.  There is a lot of guesswork in figuring out just how large a genetic bottleneck is.  It all depends on the model used, and I don’t trust models in general.  I’ve seen too many crash and burn. (For details — https://luysii.wordpress.com/2019/03/03/i-mistrust-models-2/)

However, the Neuron paper contains a reference to another paper which provides excellent empiric evidence for a small founder population, (PLoS Genet. 14, e1007329. 2018).  Here’s a direct quote.  It’s quite a mouthful; I’ll try to explain below the quote what the terms mean, because I think many nonscientific types are likely to be interested in the idea that Ashkenazi Jews are that inbred. 

Just skip the paragraph if it’s incomprehensible, go to *** and read the explanatory material, and then read the paragraph again. 

“We estimate that 34% of protein-coding alleles present in the Ashkenazi Jewish population at frequencies greater than 0.2% are significantly more frequent (mean 15-fold) than their maximum frequency observed in other reference populations. Arising via a well-described founder effect approximately 30 generations ago, this catalog of enriched alleles can contribute to differences in genetic risk and overall prevalence of diseases between populations.”

****

Explanatory material.

Our genetic material (DNA) is made of 4 different compounds A, T, G, C (called nucleotides) which are linked together in chromosomes.  The order is crucial, just as the order of letters in a word is crucial for meaning (consider united and untied).  So how many slots for the nucleotides are there in our genome ? Just 3,200,000,000.  Just as combinations of dots and dashes code for letters in Morse code, combinations of  3 nucleotides code for the 20 amino acids that make up proteins. 

Proteins are big.  For instance, the protein  (beta-globin)mutated in sickle cell anemia contains 146 amino acids, and all it takes to produce the disease is a switch from one amino acid to another at position six.  The other 145 amino acids in the chain are unchanged. So sickle cell beta globin with a change in its nucleotide sequence is an allele (alternate form) of normal beta globin.  

Every population of people contains alleles of every protein.  Some are common (over 5% of the population showing them), but most are rare.The PLoS paper looked at  73,228 alleles of all 20,000 or so proteins that we have in our genome (yes technology now can do these sorts of things) in the general population.  The authors looked at the alleles in the Ashkenazi population which were present at greater than 1/500 (.2%).  Then they looked at the frequency of the same allele in several other non-Ashkenazi population (about 5000 each of non-Finnish Europeans, African Blacks and Latinos), and found that these alleles occurred15 times less frequently (on average).   So Ashkenazi’s have alleles that are lots more common than in other populations.  Actually it’s more than some, because about 1/3 of the alleles they studied are an average of 15 times as common.

What does this mean?  It means that when a small founder population with a rare allele becomes ‘fruitful and multiplies’, the rare allele will multiply right along with it and not be lost by outbreeding (which was certainly true of the Ashkenazis for 600 of the last 750 years).

Now read the paragraph in bold above again. 

This is the evidence that current day Ashkenazi’s come from a very small founder population.  It’s pretty good.  I hope that I’ve made this somewhat comprehensible;  if not, please write a comment.

The wages of inbreeding

Saguenay Lac St. Jean is a beautiful region of Quebec. It’s fairly isolated. Once you get to the top of the lake there is no way that you can drive farther north (no road).  We spent part of our 25th anniversary there.  The population bears a heavy load of genetic disease (through no fault of their own).

The reason is historical. Only 8,000 people emigrated from France to Quebec between 1608 and 1763. After the English victory that year  only 1,000 emigrated in the next 90 years.  In 1992, the population of the Saguenay  region was around 300,000 and Quebec itself 2,000,000.

This means that once the population began expanding with relatively little outside input, recessive genes began to meet each other, as in a large population there are so many more ways to make this happen than in a small one.

To keep the the nonBiologists reading this aboard, here is what recessive means. Our genome has 46 chromosomes.  We all have two sex chromosomes (either X and Y or X and X).  The other 44 chromosomes come in pairs.  This gives you two copies of each gene.  The classic recessive gene is that for sickle cell anemia.  If just one of the pair has the Sickle trait you are OK, if both have it, you have sickle cell anemia (which you definitely don’t want to have).  Actually if you live in Africa it is better if you have one gene with the trait as it makes you more resistant to Malaria.  This is why the trait became so common in Africans.  It’s natural selection in action (and in a human population to boot).  Just one good sickle gene (not carrying the trait) is enough to mask the effects of the bad gene, so the carrier is normal.   This is why sickle cell trait is called a recessive gene.

Here is one example.  The incidence of a muscle disease (myotonic dystrophy) worldwide is 2 – 14/100,000.  In the Saguenay region it is 189/100,000.

Even 20 years ago, the carrier frequency of many genetic disorders up there was quite high [ Proc. Natl. Acad. Sci. vol. 95 pp. 15140 – 15144 ’98 ]

Spastic ataxia 1/21

Type I tyrosinemia 1/22

Sensorimotor polyneuropathy 1/23

Pseudovitamin D deficient rickets 1/26

Cytochrome C oxidase deficiency 1/26

Cystinosis 1/39

Histidase 1/32

Lipoprotein lipase 1/43

Pyruvic kinase 1/64

Then again, there are all sorts of genetic diseases found only in this region.

Similar conditions may apply to the ancestors of today’s native Americans — for details see the previous post — https://luysii.wordpress.com/2019/07/16/the-initial-native-americans-were-quite-inbred/.  Incredible as it may sound, the rape and pillage of the conquistadores may have actually been good from a genetic point of view.  Similar considerations may apply to any pair of populations meeting each other for the first time.  Hard stuff indeed, but you can’t repeal biology.

So, from a genetic point of view, it’s good if you reproduce with someone from a different group.  It’s why I’m glad to have a Chinese daughter in law, 2 grand-nephews whose father is Hindu, and a Russian woman about to marry our nephew.