SNPs are Us

It won’t be long before snp is added to the pantheon of approved English words in the OED. It will sit among those rarest of words, those that lack a vowel like the crafty Welsh invented—cwm (a mountain hollow), crwth (kind of violin), and cwtch (cubby hole or cuddle). We do of course insert an invisible i to make the word easier to say, but there will still be confusion for a word that began life as an abbreviation (single nucleotide polymorphism) and is the same as SNP (Scottish National Party). There is room for misunderstanding too, like the occasion when a woman asks a man if he got the results for his snps (meaning DNA) which he mishears as snips (and interprets as vasectomy). Language is wonderful, and so is modern genetics.

In the last post, I described my experience with DNA ancestry testing, and this time I’ll mention the health data that can be obtained. In 2013, the US Food and Drug Administration stalled the delivery of personalized genomic information, although that relaxed this month and 23andme have released potentially sensitive information to consumers. But we can dig much deeper after sending raw data file from our DNA chip analysis to another service.

The curious customer only has to invest $5 on top of the $100-200 already paid by uploading data to Promethease, a company that takes its name from the Greek deity that stole fire from the gods (customer beware!). Your results are delivered as a zip file a few minutes after uploading your genomics data, enough to pore over for hours. My file contains 17,844 annotated genotypes or snps which are doublets from the four-letter DNA code (A,T, G & C) for which there are about ten million variants across our 23 pairs of chromosomes in the population, most in the non-coding region (i.e. not in a gene sequence). Sometimes, a switch from, say, a G to a C in a DNA strand has a deadly or life-altering impact, but more often it is neutral or only predicts a certain kind of trait or disease with a percentage probability. I was eager for my data, and maybe the experience I describe will encourage others.

The large file received from Promethease was divided into categories, each with a list of snps in descending order of significance. Those highly associated with a trait were highlighted in red for scanning the good/ bad stuff quickly. The snps and genosets (snp combinations that have a more proven connection with traits) near the bottom of the lists were boring because the associations were so weak (just a few % + or -).

Let’s start with the GOOD category. This is how the first page appears.

Promethease DNA analysis
My Good News

With so much information I have to write telegraphically and hope I don’t lose the gist for readers. I was informed that I am male, white and probably of European ancestry (well, yes!). I have snps for dark eyes and blood group O (Y), a big head and higher IQ (of course), able to digest milk lactose (Y), tolerant of caffeine and my face doesn’t flush after alcohol (YY), can smell asparagus metabolites in my urine (Y), have mixed muscle types like a sprinter (eh?), won’t go completely bald (yea), have longer telomeres for long life (yipee), less endometriosis (well!), protected from headhunters’ prion disease (phew),have  lower risk of macular degeneration, diabetes, AF, obesity, various cancers (thankfully), and restless legs syndrome (mother’s problem). A lot to be thankful for until I read the next category.

Now here’s the BAD news, and an example from that first page.

Promethease DNA
My Bad Stuff

I have snps that put me at risk of cancer, diabetes, AF, lower IQ, shorter lifespan, baldness, and macular degeneration (do they cancel the good marks above). I have a 3x risk of obesity (really!), am less empathetic (I am sorry), a later menopause (phew), and have a 4x risk of sexual dysfunction if I take SSRIs (don’t ask).

Some of the little details were telling, like the results for caffeine, asparagus and the taste of cilantro/ coriander (it doesn’t taste of soap to me), as well as my earwax and body odor which I assure you are fine! I was also correctly predicted not to have a cleft chin, hairy back, unibrow or widow’s peak, and was amazed to read that my second toe is longer than my big toe. How could they know when I don’t upload my mug and feet on my Facebook page! But occasionally a result really jarred. I am proud of the dimples they missed, and with a BMI of 21 surely I can’t be obese! Other results smudged from Good to Bad, particularly heart disease, and cancers because there are so many snps. Their magnitudes were rarely more than 3x and mostly a lot lower than 2x, not much to worry about if you take the broad picture rather than lingering on one “bad” result.

I was particularly interested in the newly released information on carrier status. It is estimated that on average we all have a copy of a recessive lethal gene. One copy is quite tolerable unless you plan to be a parent and your partner is found to have a matching mutation. 23andme provides a report on 36 genetic diseases, most of them very rare but also cystic fibrosis and Tay-Sachs. You have to go elsewhere to check status for the rather too common mutations that cause breast cancer, heart and Alzheimer diseases at early ages. Not everyone wants to know, and a positive result should lead to the door of a health professional for advice.

As health and genetics data are mined more deeply and integratively I will return to my data to see how interpretations have changed. I wrote last time that genetics is not destiny. Possessing one or even a bunch of undesirable snps is not necessarily bad news because most of the traits that worry us involve hundreds of genes. Besides, they are affected by lifestyle and environment as well as our genotype. We no longer think of nature versus nurture, but nature and nurture. In a recent Australian twin study of 18,000 traits the ratio of responsibility was close to 50:50. Tragically, however, there are single gene defects where one letter of the DNA alphabet has devastating effects, and diseases affecting nerves, eyes, and bones are more affected by genetics (bipolar disease at 70%), but mental attitudes are hardly affected at all.

Snp may be a short word with a specific meaning, but it doesn’t always make genetic sense. Nevertheless, surfing snps can fill your evening with entertainment and, unless you are a hypochondriac, is a lot less scary than checking your stocks on the Dow or FTSE Index this week.

Any Comments about your experiences with these tests?

Next Post: A Mastodon in Our Town


From DNA to New Cousins & Ancestry

The back of a Cornflakes box is a good deal more absorbing than another person’s family tree. Genealogy is a rather personal game of history. Our interest seems to gain momentum with age, which may unfortunately mean we are too late for an older generation to explain gaps in our family history.

Surveys show the majority don’t know or remember or care about the names of our great grandparents or further back; perhaps we need to put a face on an ancestor for a name to mean something. As one of that majority, I knew little about my background or where my ancestors lived and are buried. But searching for records through online ancestry services and discovering remote cousins using DNA hooked me in a way that poring over parish records or deciphering gravestones never could. Technology is making genealogy into a new craze and for absorbing TV, like Finding Your Roots and Who Do You Think You Are? This post is mainly for people who want to dig up their ancestors but haven’t yet gotten started. It won’t say much about my family tree (I promise), but aims to convey what I found interesting or worrying after enrolling in Ancestry, 23andme, and Family Tree DNA. Yes, I signed up for all three because they are not exactly the same services, and I wanted to check if results were the same.

After paying the one-off sign-up fee or subscription, each company mails the customer a specimen pack to be returned with a cheek swab or spittle sample for DNA analysis. You have the option of contributing your data to the company’s genetic diversity studies (I did) and keeping your data private from other subscribers (I didn’t because I wanted unknown relatives to find me). A few weeks later an email announces your results are ready for perusal online.

If asked, I would probably say ethnicity doesn’t matter a whole lot to me. That sounds virtuous, doesn’t it, but I admit it was the first result I checked, along with predictions of my physical characteristics. Perhaps deep down there was a sliver of anxiety in case I was never told my full story, but DNA would be truthful. The data showed I am 98% Northern European. It predicted brown eyes, undetached earlobes, no cleft in my chin or wet earwax, and that I can smell sulfurous metabolites in my urine after eating asparagus. I didn’t need to spend a hundred bucks to learn what I already knew, but these confirmations gave me confidence in the other results.

Aside from 263 genetic variants handed down from my Neanderthal ancestors (blogpost of November 18, 2014), I found the mix of European origins that made me was rather interesting. I am like one of my mother’s cake recipes, made of every kind of fruit and nut plus a smack of Oriental spice. That’s common for Brits. I have an admixture of DNA from the British Isles and Ireland, a fair amount from Scandinavia (those Vikings and Danes), a little Western European (French and German), and a dab of Southern European (2%) and Middle Eastern, probably Ashkenazi Jewish (<2%).

Map my origins
Map my origins

Although all three tests confirmed European ancestry (98-100%), there was a lot of variation within that category, especially for the British Isles (14/52/69%) and Scandinavia (6/7/27%). The differences definitely reflected the haplotypes selected for testing by the companies, but also perhaps the definition of what a national origin means. It’s hard to define what it takes to be 100% “British.” Would that imply an ancestry strictly prior to the Norman Conquest (not much French), or before the Scandinavian and Saxon invasions (no Norwegian, Swedish, Danish or German heritage), or afore the Roman Conquest (no Italians or their allies)? If so, only an Ancient Briton or Celt would qualify, and I very much doubt any exist today. Besides, a strict definition might exclude that most glorious “English” king, Alfred. The companies are silent on this question, so you can choose what you want to think. If your roots are in America, north or south, you will probably have an even larger smorgasbord of origins. Congratulations!

A mixed origin is biologically reassuring and makes nonsense of some kinds of ethnic pride. There was a time and place in history when ethnicity was undiluted by recent immigration, but hard to find today.

Mum_and_Dad_headstone_1Ancestry research using DNA is greatly helped if you have data from both parents, although even if they are not available your own results can say something about their backgrounds. The mitochondrial genome is a tiny ring of DNA inherited from our mothers, and we share it with our brothers and sisters. My maternal haplogroup is K1a11 which originates in the Middle East and traveled to Europe through the relatives of Otzi the Ice Man. My brothers and I inherit our father’s haplogroup I1 from his Y chromosome, which is common in Scandinavia. None of us is blond and blue-eyed, and none have the financial sagacity of Warren Buffett who has the same haplotype. It’s not surprising.

Genetics is not destiny, not really. Scientific or artistic genius very rarely run in families, and hardly ever more than two generations. And consider Bill Maher and Bill O’Reilly, one a leftish political satirist and the other a host on Fox News Channel. They are at opposite poles of the political spectrum, yet have a common Irish ancestor way back. No surprise there either, but I digress.

The longer you are an active subscriber to a genealogical service the more information that rolls in because other people join and some become sharers. If you go public with data, you will soon see your DNA matching other people’s and learn the strength of the match (%) and the corresponding segments (in cM). Your parent or child should of course have a 50% DNA match with you, but after gaining that reassurance it’s most interesting to scroll through the lower entries. There are likely to be hundreds of other matches in descending order of relatedness. Some of them provide a picture and short bio, and even an email for contacting them, but most on your list are likely to be anonymous or never reply to your inquiries. I suspect they don’t have anything to hide: they enrolled mainly for the health data that can be downloaded (next post) or never return to the page for updating DNA relatives.

You will undoubtedly have some surprises. For me it was the large number of American matches, more than any other nationality, because I had no idea about any ancestors migrating ahead of me. As for the British people expected to be on my list, perhaps they are more wary of sharing details in case they reach a nosy government or genetic stalkers.

My wife had the happy discovery of an unknown third cousin through a DNA match. She lives only an hour away from us and owns property that their common ancestor farmed in the early days of Colonial America. She is a super cousin because they share over 1% of their DNA, meaning they might be doubly descended from their ancestor. Lucinda is also distantly related to her daughter-in-law’s family. My surprise was to find my wife’s half-sister and brothers in Texas are my remote cousins, probably through an Irish ancestor I never knew about.

You have to be ready for a jolt when you delve into history, and I’m still waiting for one. Luckily, I haven’t found any felons or slave-owners in my family tree, nor relatives of that man with a black toothbrush mustache who died in 1945. Phew! But be prepared to hear from people trying to find living relatives. Two women who were adopted as children have contacted me, but I couldn’t give them any leads to a living parent or sibling because we are too distantly related. Another contact has been trying to establish a link between us and a billionaire hedge-fund owner; thankfully, that inquiry has gone silent. No doubt some people have used these services instead of standard paternity testing, and I have reason to believe an oral sample doesn’t need as much scrubbing as the instructions recommend. Padlock your toothbrush if that worries you.

Besides filling the missing names on a family tree, tracing ancestors back for say seven generations to the 17th century reveals many interesting details and documents. For example, registrations of births, marriages and deaths, military records, census data, ocean crossings and immigration data, not to mention convictions for felonies, are represented online from scanning of original documents. Perusing these materials was a moving experience because it personalized those who had contributed to my existence by revealing the little details I would never have known otherwise. There is a risk, however, that family stories that have grown fonder in the telling through the generations can turn out to be flawed or fanciful, so prepare for dissonant emotions.

One person who contacted me was searching for a royal connection, so I was glad I couldn’t help her. She left me wondering why anyone wants to be connected to a lineage that is marred by an unhealthy degree of inbreeding in the past. Remember hemophilia was passed down by Victoria, and the famous jaw of the Royal House of Habsburg? European royal families constantly intermarried. Queen Victoria married her first cousin, Prince Albert of Saxe-Coburg, an admirable and brilliant man whom anyone would be proud to call a relative. But whatever parts of the genome contributing to his gifts (probably minor) were mixed and diluted in the following generations. A dynasty endures through its heirs, but not by passing down a founder’s peculiar genetic merits.

Lastly, I was musing about King Richard III, the last of the Plantagenet kings of England who was killed at the Battle of Bosworth Field in 1485. The grave was excavated in a Leicester carpark in 2013 and his identity was confirmed from DNA and spinal curvature. Ricardians strive to repair his reputation brought down by Shakespeare, and in some circles there is a cachet if you can prove descent from Good King Richard.

Think about it. He lived over 21 generations ago. If you can trace your branches back to the trunk that connects to his close relatives (he had no children) you have a claim to the Plantagenet crown, but it’s vanishingly slender. DNA is diluted by half at every new generation, so if we assume no interference by intermarriage or asymmetric recombination or medieval milkman (some assumptions!), you share 221 of his DNA, or less than one part in a million. It is meaningless to feel honored by descent from some bigwig if he or she is that remote. But there is a wonderful conclusion here: ancestry research reminds us we are all connected, and if we need to boast we can all claim a relationship to our greatest heroes in history. It’s all a matter of degree, because we are all cousins.

Next Post: What Price Genetic Privacy?


My Big Fat Neanderthal Family Wedding

Was there a population that never experienced discrimination?  Prejudice has an ancient pedigree, perhaps wired into the human psyche. I was musing whether Neanderthal people bore it first and endured the stigma longest.  Thirty thousand years after they mysteriously disappeared, they are still regarded as oafish cavemen.

But at least we regard them as human, while ridiculing their long noses, brow-ridges, and prow-mouths. Besides the evidence of fossilized skeletons and DNA, I wonder if their humanity is also defined by our prejudicial attitudes, because we only look down on our own kind. We never hold animals in the same contempt as people, because even the great apes are subordinate beasts! It is not because other people are so different that we discriminate, but because they are too similar. When we look down our noses at other races, both archaic and modern, we reveal our deeper insecurities, and perhaps anxieties about losing superiority and being swamped.

Social scientists and anthropologists have not always been totally objective in their estimation of other tribes and races. I doubt there was ever a researcher who found his own race was inferior in character or intelligence to another, or if he did he never published it!

Sometimes people who know better don’t admit the facts. Over twenty years ago, my department hosted a distinguished British anatomist, who shall be nameless. He denied that Neanderthals had a slightly larger cranial volume (hence, brain size) than ourselves. It was useless arguing with him because he was a ‘Sir’ and a Fellow of the Royal Society. If he had admitted that their larger brain was merely in proportion to a larger body, we might have drawn a truce rather than ending the exchange in sulky silence. But he refused to discuss the hypothesis that they might have been our equals.

Neanderthal skull versus modern human skull
How much does size matter?

Poor Neanderthals need publicity agents to throw back slurs based on ignorance. There is so much we don’t know, and may never know. Did our first great encounter with these people begin with the exchange of gifts or at the point of a spear? According to a common fairy story, the dim Neanderthals were doomed when our brilliant ancestors arrived on the scene. We flatter ourselves with triumphal tales, even though this one is grotesquely reminiscent of the way we treated people when colonizing their lands, subjugating them in the name of civilizing inferior natives.

On the first world voyage of H.M.S. Beagle (1826-1830), FitzRoy captured three natives in Tierra del Fuego and took them home to England. The Fuegians were dressed up as English folk, taught the language, instructed in the Christian faith, and even presented to the Royal Family. On the second voyage, with Charles Darwin as ship’s naturalist, the three were returned to their homeland where they quickly reverted to custom by throwing away their clothes and painting their skin with pigments. FitzRoy thought this behavior vindicated his theory that the gulf with civilized nations is too deep to cross.  Savages will always be savages, and always inferior.

Charles Darwin
Charles Darwin’s cranium – Neo-anderthal?

On the other hand, Darwin, an old-fashioned Whig or liberal, was awed by the mystery, “Whence have they come?” He accepted a hierarchy of human races, but believed it was moveable. He disagreed with Captain Fitzroy about most things, including slavery, which must have been awkward on a long voyage in a shared cabin. After they sailed home, immigrants started colonizing the southern tip of the continent. They treated the natives as feral humans, and those that survived epidemic diseases were otherwise exterminated.

Years later, Darwin was shown a skull excavated from a cave in Gibraltar (and is now at the Natural History Museum in London). This was the first fossil of an adult Neanderthal, and it predates by eight years another find in the Neander Valley which gave the people their name. Instead of sharing the general opinion that it represented a primitive brute, he cautioned, “Light will be thrown on the origin of man and his history.”  Human genealogy has rolled out slowly since his day because our fossils are rare, but molecular genetics reveals branches on our family tree that challenge the stories we were told.

Recently, pure DNA was extracted from fossil bones to obtain a nearly complete sequence of the Neanderthal genome. I doubt if many people expected that between one and four per cent overlaps the genomes of modern Europeans and Asians. Today’s Africans have none of it though, which implies that the fraction possessed by the rest of humanity is not a residue from a common ancestor hundreds of thousands of years earlier. That Neanderthal DNA exists in us today is because our ancestors coming out of Africa about 50,000 years ago met Neanderthals living in the Middle East, with whom they intermarried (call the coupling what you will). Fossil evidence confirms that we did co-exist with them for 5,000 years, so there was plenty of time for integration, and our Neanderthal heritage is not the result of sporadic mating. I guess it was mostly consensual because I find it hard to imagine a Neanderthal woman being carted away unwillingly from her menfolk, who were like the beefiest NFL players you could imagine! But I digress.

Analysis of my own DNA reveals that I inherited 2.7% from Neanderthals. That is close to average for my ethnicity, and more than I share with my third cousins. The news amused me until I mused that it was ‘good DNA,’ for otherwise it would never have lasted so long after the weddings. Some bits of the genome have persisted more than others. We have acquired many genes associated with skin and hair, which implies that Neanderthal adaptations to cold were advantageous for our ancestors too when the next Ice Age arrived. However, we also hung on to genes linked with modern diseases, which seems perverse. Perhaps they were not so bad in the past before we adopted our current lifestyle and diet. Genes encouraging fat storage, but predisposing us to adult-type diabetes and obesity, might have helped us to survive cycles of feast and famine, perhaps thanks to ‘thrifty DNA’ from Neanderthals.

The number of generations separating races of modern people from our common African ancestors is like a twig on the evolutionary tree compared with the much older branches shared with Neanderthals from whom we separated over half a million years earlier. Neanderthals are our cousins, but mutations and natural selection caused genomes to drift so far apart that geneticists suspect that hybridization was barely viable. When crosses are made between closely-related species like horses and donkeys, the products are usually sterile if any offspring can be produced at all. That hybrid humans may have had fertility problems is suggested by the absence of Neanderthal DNA in our genes that control the manufacture of sperm in testes. Perhaps it didn’t ‘fit’ there, and maybe absorption of Neanderthals into the new society contributed to their disappearance.

If the image of a Neanderthal man courting your beautiful greatetc-grandmother is repulsive, look at sculptures by the American paleo-artist, John Gurche. His art is based on careful studies of the physiognomy of archaic humans. He created a Neanderthal profile which is imposing, almost handsome, even noble.

The Phrenological magazine

Appearance matters, but intelligence often carries greater weight in our estimation of others. In the Victorian Age, phrenology was in vogue and its adherents trotted around the globe measuring the size and shape of skulls of rich and poor, saints and sinners, civilized nations and primitive tribes. They expected these measurements would predict people who were inferior in character and intellect, who always turned out to be the most disadvantaged in their studies. The discovery of Neanderthal bones gave them a new opportunity for skullduggery. In 1880, The Phrenological magazine declared, “The Cro-Magnon skull is superior to the Neanderthal skull in regard to intellectual and moral development … he was indeed a savage.” We may never know for sure, but I doubt that Neanderthals were dim people, or less bright than ourselves. That may seem contrary to signs that their tools and culture hardly evolved over eons, but neither did those of our ancestors advance much until the recent Agricultural Revolution. Could Neanderthals have struck a smarter deal, opting for a more stable relationship with nature than we have?

The German lion of Darwinism, Ernst Haeckel (1834-1919), would be flustered by modern research and scholarship because he suggested that Neanderthals should be called Homo stupidus to distinguish them from our brilliant selves, Homo sapiens (literally, ‘wise man’). It was a proposal that revealed prejudice, but our cousins had fortunately been named already, and precedent counts in taxonomy. They were designated a new species, Homo neanderthalensis, although taxonomists continue to argue whether they were a distinct species or the subspecies, Homo sapiens neanderthalensis. I don’t understand the debate. To be a separate species, two populations must be reproductively isolated, either genetically (they can’t mate with each other) or geographically (they can’t hang out with each other). Since Neanderthal DNA exists in our genome, they ought to be regarded as a sub-species: more different than modern races are from each other, but inside the species fence.

The popular image of Neanderthals is gradually being turned upside down by advances in traditional and molecular paleontology. Contrary to the stereotypes, we now know they were fair-skinned with reddish hair, not strict carnivores but ate a mixed diet with cooked vegetables, probably had a language, and evidently created symbolic art on stone walls and decorated their bodies. Most touching of all is the suggestion of a tender humanity, and that they were not emotional icebergs. Since some of their skeletons have badly worn joints and are almost toothless, these people probably needed carers to help them to survive with disabilities. After death, their bodies were not discarded like carcasses of game animals, but given a respectful burial. Can you imagine last rites performed by a Neanderthal shaman?

This revisionary anthropology throws refreshing light on a maligned people, although over a century ago a Danish anthropologist, Hans Peter Steensby, rejected the impression of Neanderthals as ape-like, inferior beings. But prejudice is deeply imbedded, and despite efforts to exorcize the demon we easily express it unconsciously. The other day, I caught myself joking that I have less Neanderthal DNA than the rest of my family!

Next Post: Thanks given for Wild Turkeys