The US military is funding research to predict who will get sick when suddenly transported to high altitude locations (e.g. by parachuting onto a mountain). The latest round of research will try to verify an earlier round that identified 6 genetic variants that appear to predict who will do worse at high altitude.
Robert Roach, who directs the Altitude Research Center at the University of Colorado, performed a similar test last year, taking 28 research subjects to a simulated altitude of 16,000 feet by putting them in a special chamber that mimics the effect of a low-oxygen environment. A blood test, screening for those six genetic elements, was able to predict with 96% accuracy which of the 28 would fall ill.
The researchers hope their research will ultimately lead to the development of drugs that cause human metabolisms to adapt to high altitudes. But drug development typically takes many years and many hundreds of millions of dollars. Not all drug development efforts succeed and many drugs on the market have side effects that one should avoid risking unless absolutely necessary.
Since drug development is a distant prospect genetic testing to select rapid adapters would seem a more practical way to the knowledge garnered from this research. If genetic testing can predict which soldiers have the best prospects to hit the ground running (and shooting) then for high altitude jobs why not just send the soldiers whose genetic profiles indicate they can handle it?
Some groups (e.g. Tibetans) carry genetic variants that adapt them especially well to high altitude living. Once those genetic variants are identified those genetic variants are probably rare outside of groups that have lived at high altitudes for many centuries. But gene therapies, cell therapies, and tissue engineering techniques will provide ways to basically do software upgrades.
Adjustment to altitude is just one of many types of genetically determined capabilities that will get genetically screened for in the future. Where it will get especially interesting: offspring genetic engineering. This isn't just about muscles, beauty, and intelligence. As this report above demonstrates, many other genetic adaptations are possible. So will parents choose genes optimized for high or low altitude living? For cold or warm or moderate temperature? For low tendency for distraction to allow more sustained abstract reasoning or for higher tendency for distraction to be more responsive to other people or to dangers?
To search for genetic variants associated with adult height, researchers performed a complex genetic analysis of more than 100,000 individuals. "We set out to replicate previous genetic associations with height and to find relevant genomic locations not previously thought to underpin this complex trait" explains Dr. Brendan Keating, also from The Children's Hospital of Philadelphia. The authors report that they identified 64 height-associated variants, two of which would not have been observed without such a large sample size and the inclusion of direct genotyping of uncommon single-nucleotide polymorphisms (SNPs). A SNP is a variation in just one nucleotide of a genetic sequence; think of it as a spelling change affecting just one letter in an uncommonly long word.
Note the number of height-associated variants. The reason it has taken so long to make use of genetic sequencing data is that many different variants each contribute to height, personality, disease incidence, and other attributes and risks. Since each variant contributes so little a large number of subjects must be used to detect the various small contributors.
I want the search for the meaning of genetic variants to go much faster. With prices for personal genetic testing getting pretty cheap I'm intrigued by the prospect that lots of individuals can pay affordable prices to get themselves tested and also enter health info onto a web form to participate in scientific research into the meaning of genetic variations. This holds the promise of greatly lowering the cost of research while speeding up the rate of discoveries.
The first phase of the study includes development and validation of web-based surveys to assess the drug side effects and drug effectiveness experienced directly by 23andMe's customers. During the second phase, the research team will determine whether this approach enables them to replicate previously known associations between response to these three classes of drugs and variation within two genes: CYP2C9 and CYP2C19. 23andMe's research team will also search for previously unknown genetic factors associated with response to these classes of drugs, taking into consideration a broad range of non-genetic factors such as age, sex, and body-mass index, among others.
In previous studies, 23andMe has demonstrated that self-reported information from customers yields data of quality comparable to that gathered using traditional research methods.
23andMe's new gene chip tests about 1 million locations on genes where variations occur. Suppose a few hundred thousand people sign up for their service and then also enter in lots of information (e.g. height, eye color, hair color, weight, assorted other physical measurements, history of allergies, asthma, injuries, drug reactions, and other events and maladies). The influences of large numbers of genetic variants could be discovered.
Lots of discoveries are waiting to be made using cheap gene chips to collect data on lots of known single letter genetic variants. After that flood of genetic data comes an even bigger flood. While sequencing the first complete genome took years and hundreds of millions of dollars the costs have now fallen into the tens of thousands (if not lower) per genome. With these low costs the rate of full genome sequencing has now reached hundreds per quarter and therefore over one thousand per year. We can expect the rate to go up by more orders of magnitude.
Complete Genomics said last week that it anticipates sequencing more than 300 human genomes in the fourth quarter of 2010.
Full genome sequencing allows identification of extremely rare genetic variants and also the measurement of large copy variations and other genetic variants not easily captured by gene chips. But data the gene chips alone, used by hundreds of thousands and even millions of people and combined with personal data, will allow scientists to identify at least tens of thousands of genetic variants that influence who we are.
Pat Benatar was more right than we knew. Love is a battlefield.
CAMBRIDGE, Mass., July 28, 2009 -- An analysis of rare genetic disorders in which children lack some genes from one parent suggests that maternal and paternal genes engage in a subtle tug-of-war well into childhood, and possibly as late as the onset of puberty.
This striking new variety of intra-family conflict, described this week in the Proceedings of the National Academy of Sciences, is the latest wrinkle in the two-decades-old theory known as genomic imprinting, which holds that each parent contributes genes that seek to nudge his or her children's development in a direction most favorable, and least costly, to that parent.
"Compared to other primates, human babies are weaned quite early, yet take a very long time to reach full nutritional independence and sexual maturity," says author David Haig, George Putnam Professor of Organismic and Evolutionary Biology in Harvard University's Faculty of Arts and Sciences. "Human mothers are also unusual among primates in that they often care for more than one child at a time. Evidence from disorders of genomic imprinting suggests that maternal and paternal genes may skirmish over the pace of human development."
So our genes are fighting it out. Will mom or dad's genes rule the liver? Whose genes will capture the high ground of the brain? Will the loser at least manage to hold onto the colon or kidneys?
Whilst we all know that tall parents are more likely to have tall children, scientists have been unable to identify any common genes that make people taller than others. Now, however, scientists have identified the first gene, known as HMGA2, a common variant of which directly influences height.
The difference in height between a person carrying two copies of the variant and a person carrying no copies is just under 1cm in height, so does not on its own explain the range of heights across the population. However, the researchers believe the findings may prove important.
Previous studies have suggested that, unlike conditions such as obesity, which is caused by a mix of genetic and environmental factors – so called "nature and nurture" – 90% of normal variation in human height is due to genetic factors rather than, for example, diet. However, other than very rare gene variants that affect height in only a small number of people, no common gene variants have until now been identified.
The research was led by Dr Tim Frayling from the Peninsula Medical School, Exeter, Professor Mark McCarthy from the University of Oxford and Dr Joel Hirschhorn from the Broad Institute of Harvard and MIT in Cambridge, US. Dr Frayling and Professor McCarthy were also part of a Wellcome Trust-funded study team that discovered the first common gene linked to obesity in April this year.
We are just now starting to see the results of big drops in the cost of DNA testing. The rate of discovery of the meaning of genetic variations is about to turn into a torrent. The discoveries will come so fast that only the most interesting ones will garner any press attention.
The findings, published in the September 2 advance online edition of Nature Genetics, stem from a large-scale effort led by scientists at the Broad Institute of Harvard and MIT, Children’s Hospital Boston, the University of Oxford and Peninsula Medical School, Exeter. Using a new “genome-wide association” method, the research team searched the human genome for single letter differences in the genetic code that appear more often in tall individuals compared to shorter individuals. By analyzing DNA from nearly 35,000 people, the researchers zeroed in on a difference in the HMGA2 gene — a ‘C’ written in the DNA code instead of a ‘T’. Inheriting the ‘C’-containing copy of the gene often makes people taller: one copy can add about a half centimeter in height while two copies can add almost a full centimeter.
These scientists think this gene's variants account for just 0.3% of all variability in human height. So many more genes that contribute to height are waiting to be found.
The genomic find, though, is not the only indication that HMGA2 affects height. Previous studies in mice and humans revealed that a handful of rare stature disorders result from severe mutations in the gene. Taken together, the findings provide strong evidence for a role for HMGA2 in height. However, the identified SNP accounts for just 0.3% of the normal variability in human stature, which means there are probably many others yet to be found. To do this, researchers will need to study even larger groups of individuals.
Imagine what happens when we discover all the genetic variations that influence height. A couple gets their DNA sequenced. A genetic counselor tells them if they have a son he could be anywhere from 5' 6" to 5' 11". But if they produce a dozen in vitro fertilization (IVF) embryos they've got a very high chance of getting a couple of embryos on the tall end. Suddenly IVF becomes a lot more attractive.
How far are we away from the deluge of genetic sequencing discoveries and the beginning of the shift toward IVF as the preferred way to start pregnancies? Maybe 5 years.
Having brought the cost down by three orders of magnitude, the aim is to drop it by another three, to $1,000, and also to speed things up. To that end, the X Prize Foundation, an innovative American charity, is offering a $10m prize to the first team to decode the DNA of a hundred people within ten days. Dozens of groups from around the world have signed up, and the organisers expect a winner in less than five years. And it may not take that long. George Church of Harvard University recently started what he calls the Personal Genome Project. This aims to decode the genetic material of 100,000 people over the next year or so.
We haven't even seen the full discovery effects of the last few orders of magnitude in DNA sequencing costs. The costs have dropped too recently for researchers to have made much use of the new affordability of genetic sequencing. Once the costs drop a few more orders of magnitude full genome sequencing of millions of people will become affordable and then will come the deluge of discoveries of what all the genetic variations mean.
Early DNA sequencing and testing technology made it easier to find single point mutations where just a single DNA letter is different. Now scientists are employing techniques that allow identification of larger scale differences where big sections of the genome show up as multiple copies and the number of copies varies between people. At least 10% of human genes vary between people in the number of internal sequences or whole genes that are found in each person.
New research shows that at least 10 percent of genes in the human population can vary in the number of copies of DNA sequences they contain—a finding that alters current thinking that the DNA of any two humans is 99.9 percent similar in content and identity.
I never bought into the politically correct claims from figures around the human genome project a few years ago about how genetically similar we all are. Humans have evolved in too many local environments with unique selective pressures for that to be the case. Even this paper does not uncover the full extent of genetic variation in the human species. Expect to see more such reports.
This discovery of the extent of genetic variation, by Howard Hughes Medical Institute (HHMI) international research scholar Stephen W. Scherer, and colleagues, is expected to change the way researchers think about genetic diseases and human evolution.
The idea that large copy variations exist is not new news. Reports have been coming out over the last few years suggesting that copy variations play a big role. But this is the first report I'm aware of that tries to more comprehensively measure the extent of human genetic variation due to copy variations. Note again that Scherer's group has not discovered all such genetic variations. Their sample size of only 270 people from 3 races doesn't begin to capture the extent of the variation within each race let alone the variations in Amerinds, Australian Aborigines, and other groups. Plus, their technique for detecting copy variations probably has limitations that caused them to miss some even in the samples they studied.
Discovery of large numbers of functionally significant variations is good news for a number of reasons. The greater number of variations allows even more comparisons of humans to see how variations on each gene affect how human metabolism functions. Also, it provides indication that we need more methods of DNA testing in order to do personal genome testing.
This group found copy variations that affected 10% of all genes. But, again, this represents a lower bound on the total. The variations that are going to be harder to find are the ones that are rarer. Every person alive probably has genetic variations unique to them. We need really cheap personal DNA sequencing and DNA testing to uncover all the variations that exist.
Genes usually occur in two copies, one inherited from each parent. Scherer and colleagues found approximately 2,900 genes—more than 10 percent of the genes in the human genome—with variations in the number of copies of specific DNA segments. These differences in copy number can influence gene activity and ultimately an organism's function.
Scherer's team used DNA samples from 270 people who have given DNA to the International Hap Map project. That project is aimed at identifying single letter genetic variations and how groups of single letter variations tend to occur together. Their goal is not only to map the extent of genetic variation but also to look for ways to predict some variations due to the presence of other variations.
To get a better picture of exactly how important this type of variation is for human evolution and disease, Scherer's team compared DNA from 270 people with Asian, African, or European ancestry that had been compiled in the HapMap collection and previously used to map the single nucleotide changes in the human genome. Scherer's team mapped the number of duplicated or deleted genes, which they call copy number variations (CNVs). They reported their findings in the November 23, 2006, issue of the journal Nature.
Scherer, a geneticist at the Hospital for Sick Children and the University of Toronto, and colleagues searched for CNVs using microarray-based genome scanning techniques capable of finding changes at least 1,000 bases (nucleotides) long. A base, or nucleotide, is the fundamental building block of DNA. They found an average of 70 CNVs averaging 250,000 nucleotides in size in each DNA sample. In all, the group identified 1,447 different CNVs that collectively covered about 12 percent of the human genome and six to 19 percent of any given chromosome—far more widespread than previously thought.
Many genes linked to a variety of diseases have copy number variations (CNVs).
Not only were the changes common, they also were large. "We'd find missing pieces of DNA, some a million or so nucleotides long," Scherer said. "We used to think that if you had big changes like this, then they must be involved in disease. But we are showing that we can all have these changes."
The group found nearly 16 percent of known disease-related genes in the CNVs, including genes involved in rare genetic disorders such as DiGeorge, Angelman, Williams-Beuren, and Prader-Willi syndromes, as well as those linked with schizophrenia, cataracts, spinal muscular atrophy, and atherosclerosis.
In related research published November 23, 2006, in an advance online publication in Nature Genetics, Scherer and colleagues also compared the two human genome maps—one assembled by Celera Genomics, Inc., and one from the public Human Genome Project. They found thousands of differences.
"Other people have [compared the two human genome sequences]," Scherer said, "but they found so many differences that they mostly attributed the results to error. They couldn't believe the alterations they found might be variants between the sources of DNA being analyzed."
A lot of the differences are indeed real, and they raise a red flag, he said.
Doing individual DNA testing on copy variations is probably harder than doing it for single letter differences. But this research paper will probably cause more scientists to work on better and cheaper techniques for measuring copy variations.
Personalized genome sequencing—for individualized diagnosis, treatment, and prevention of disease—is not far off, Scherer pointed out. "The idea [behind comparing the human genome sequences] was to come up with a good understanding of what we're going to get when we do [personalized sequencing]," he explained. "This paper helps us think about how complex it will be."
Copy variations can deliver a few benefits. First off, having more copies of a gene can allow it to get expressed more rapidly. There's a limit to how fast a gene can get transcribed (read) to make messenger RNA. If more copies of the gene exist then they can get read in parallel to produce more copies of messenger RNA (mRNA) in a given amount of time. Then the mRNA gets translated into chains of amino acids which form peptides which, in turn, make up proteins or serve other roles.
Copy variations also make it possible for each copy to take get mutated to make custom versions of peptides that can do different things under different circumstances. One copy can serve the old purpose for which the gene exists and another copy can mutate to better serve some new need that has arisen.
Pittsburgh, December 1, 2004 – Specific variants in genes that encode proteins regulating inflammation may hold a key to explaining a host of disease processes known to cause increased risk of illness and death among African Americans, according to a study from the University of Pittsburgh’s Graduate School of Public Health (GSPH). The study, “Differential Distribution of Allelic Variants in Cytokine Genes Among African Americans and White Americans,” appears in the Dec. 1 issue of the American Journal of Epidemiology.
“We found that African Americans were significantly more likely to carry genetic variants known to stimulate the inflammatory response,” said Roberta B. Ness, M.D., M.P.H., professor and chair of the department of epidemiology at GSPH and the study’s primary author. “At the same time, genotypes known to dampen the release of anti-inflammatory proteins were more common among African Americans. This is kind of a double whammy.”
The genes for some major immune regulatory proteins were looked at. Note that advances in assay techniques are allowing scientists like these folks to examine many more genes at once than was done in past studies.
Specifically, scientists compared genetic data on 179 African-American and 396 white women who sought prenatal care and delivered uncomplicated, single, first births at Magee-Womens Hospital of the University of Pittsburgh Medical Center between 1997 and 2001. Blood samples were analyzed for a multitude of functionally relevant allelic variants in cytokine-regulating genes. Among these were several genes regulating the immune system proteins interleukin-1, interleukin-1 alpha, interleukin-1 beta, interleukin-6, interleukin-10, interleukin-18 and tumor necrosis factor-alpha.
“In the past, people looked at one or two variants,” said Dr. Ness. “We looked at a whole host, and saw trends that perhaps point to some evolutionary-mediated change in the human genome that has had an impact on inflammation.”
There has been a marked trend in recent years in the discovery of a major role for inflammation as a driver for the development of a large range of diseases including atherosclerosis and cancer. The anti-inflammatory COX2 inhibitor drug celecoxib (brand name Celebrex) is currently being used in a number of cancer treatment trials. Chronic inflammation accelerates the aging process. A genetic difference between groups in their propensity for inflammation is inevitably going to cause group average differences in disease incidence.
Odds ratios for African Americans versus Whites in genotypes up-regulating proinflammatory interleukin (IL) 1 (IL1A-4845G/G, IL1A-889T/T, IL1B-3957C/C, and IL1B-511A/A) ranged from 2.1 to 4.9. The proinflammatory cytokine interleukin-6 IL6-174 G/G genotype was 36.5 times (95% confidence interval (CI): 8.8, 151.9) more common among African Americans. Genotypes known to down-regulate the antiinflammatory interleukin-10 (IL10-819 T/T and IL10-1082 A/A) were elevated 3.5-fold (95% CI: 1.8, 6.6) and 2.8-fold (95% CI: 1.6, 4.9) in African Americans. Cytokine genotypes found to be more common in African-American women were consistently those that up-regulate inflammation.
Note that interleukin-19 (IL-10) is among the genes found to occur in different frequency in blacks and whites. Well, another study found that IL-10 promoter polymorphisms appear to influence the rate of advance of HIV infection. So this result also has implications for the spread of HIV and likely for vulnerability to other pathogens.
The differing frequencies of genetic variations for genes that regulate inflammation response were selected for by the radically different ecological niches humans found as they spread out around the world. Therefore it is not surprising the frequencies of variations are different in human groups which have long settled different parts of the world. What is more interesting than the differences in genetic variation frequencies (at least to me) is that it is likely that neither the frequencies of genotypes in whites or the frequency of genotypes in blacks are ideal for the environments we find ourselves living in today. Our inflammation responses are in all likelihood maladaptive for industrial society. My guess is that humans in general in modern society are experiencing more inflammation on average than is beneficial for them.
We need better smarter ways to control the inflammation response and easier ways to detect triggering of the inflammation response. Lots of people are walking around with chronic inflammation who do not even know it. Think of it as analogous to the people who are walking around with undiagnosed high blood pressure. Some people have chronic inflammation due to an undiagnosed infection. Others have it due to a nutritional deficiency (e.g lack of folic acid, B-6, and B-12 to brake down homocysteine). Still others may have it due to a low grade auto-immune response that they are unaware of. We need to be able to detect and more consciously control our inflammatory responses. But just how what sort of treatment will be optimal to exert on our inflammatory responses will depend at least in part on which particular set of genetic variations we possess for genes that regulate the inflammatory response.
The U.K. Biobank in Great Britain is going to track the health of hundreds of thousands of participants for years and then determine their genetic differences to look for genetic variations that contribute to disease.
For 10 years, they will be followed through their national health care records, which will be copied into the Biobank. The data will be anonymous, but not completely, to allow for updates by doctors or new questionnaires. By 2014, 40,175 are expected to fall ill with diabetes, heart disease, stroke or cancer. Another 6,200 are expected to have Parkinson's, dementia, rheumatoid arthritis or hip fractures. The DNA of these people will be read and compared, and any normal gene variants, the one-nucleotide differences in DNA that make one person's biology different from another's, will be tagged for study.
The cost of DNA sequencing is going to continue to fall and will fall by many orders of magnitude. It makes sense to start collecting samples and medical histories now and start tracking people for many years. Then when the cost of sequencing falls far enough it will be possible to cheaply determine the entire sequence of every person in the study and compare the data to the health histories of the participants.
However, the study is not ambitious enough. Genetics affects behavioral and personality characteristics and of course an assortment of physical performance characteristics. A really ambitious study would not just collect a representative cross-section of the population. It would also collect samples from people who have either excelled or stood out for being unique in a variety of ways. To look for genetic factors that contribute to various forms of excellence such people as Nobel Prize winners in every category, champion chess players, Olympic medal winners in every category of sport, and any others who have excelled in some measure of extreme accomplishment should be included. At the same time, people who have been maladaptive and dangerous to self or others in extreme ways (eg serial killers, self-mutilators, gambling addicts, drug addicts, and those who suffer from obsessive compuslive disorders) should be sought out for participation.
Another useful way to make the study more ambitious would be to collect more types of measureable information about each participant. For instance, personality tests, psychometric tests, and other tests of mental qualities could be done on volunteers. Also, a wide array of physical tests of coordination, endurance, and of bodily and mental responses to stresses (eg heat, cold, loud noise, being spun around) could be measured. Opinion tests on politics and even on personal preferences in food, colors, music, and other subjects could be done. In a similar vein, a detailed questionaire about hobbies and habits would yield useful information when compared against genetic sequences.
For far too long countless social science studies have been done where genetic factors were not controlled for as variables. What is needed is a massive set of test data collected on a large group of people where genetics can be controlled for along with as many other measurable qualities of people that can be imagined. This could revolutionize the social sciences. A study involviing hundreds of thousands of people that has genetic contribution to physical diseases as its main focus, as laudable as that may be, is lacking in ambition.
In evolutionary terms a mutation that arose only 20,000 years ago is pretty recent. If this is correct then the pheomelanin variation of melanin that produces red hair is pretty new.
According to the most recent estimates, the first red hair sprouted just 20,000 years ago, long after the advent of modern homo sapiens.
Well, whether your hair has (or had) eumelanin for brown and black hair or pheomelanin for yellow and red hair some day gene therapy or cell therapy will make it possible to turn gray hair back to a youthful color. Women wanting a different color will even be able to choose which type of melanin and in what quantity they want to have. Probably some adult stem cells will be able to be converted into youthful melanocytes and melanosomes:
Research suggests that we may be able to reverse the graying process in the future. Tobin's group, for instance, has determined that the dormant melanocytes and melanosomes in gray hair follicles can be coaxed into creating melanin again