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Thread: Human genome more variable than previously thought

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    Exclamation Human genome more variable than previously thought

    Human genome more variable than previously thought

    Helen Parson Nearly six years after the sequence of the human genome was sketched out, one might assume that researchers had worked out what all that DNA means. But a new investigation has left them wondering just how similar one person's genome is to another's. Geneticists have generally assumed that your string of DNA 'letters' is 99.9% identical to that of your neighbour's, with differences in the odd individual letter. These differences make each person genetically unique — influencing everything from appearance and personality to susceptibility to disease. But hold on, say the authors of a new study published in Nature. They have identified surprisingly large chunks of the genome that can differ dramatically from one person to the next. "Everyone has a unique pattern," says one of the lead authors, Matthew Hurles at the Wellcome Trust Sanger Institute in Cambridge, UK. The differences in question - made up of stretches of DNA that span tens to hundreds of thousands of chemical letters — are called 'copy-number variants', or CNVs. Within a given stretch of DNA, one person may carry one copy of a DNA segment, another may have two, three or more. The region might be completely absent from a third person's genome. And sometimes the segments are shuffled up in different ways. These variable regions received short shrift for many years. When the human genome sequence was pieced together, they were largely glossed over, because researchers were focused on finding one overarching reference sequence — and because the repetitive nature of the segments makes them hard to sequence. "It was swept under the rug," says Michael Wigler who is also mapping CNVs at Cold Spring Harbor Laboratory, New York. All change The new study, led by Hurles and Stephen Scherer of the Hospital for Sick Children in Toronto, Canada, and their colleagues is the most detailed attempt to find how CNVs are scattered across the whole human genome. To do this, they compared genome chunks from 270 people of European, African or Asian ancestry.



    Same but different 3,080 million 'letters' of DNA in the human genome 22,205 genes, by one recent estimate 10 million single-letter changes (SNPs) — that's only 0.3% of the genome 1,447 copy-number variants, covering a surprisingly large 12% of the genome

    About 99.5% similarity between two random people's DNA They found nearly 1,500 such regions, taking up some 12% of the human genome. That doesn't mean that your DNA is 12% different from mine (or 88% similar), because any two people's DNA will differ at only a handful of these spots. According to the team's back-of-the-envelope calculations, one person's DNA is probably 99.5% similar to their neighbour's. Or a bit less. "I've tried to do the calculation and it's very complicated," says Hurles. "It all depends on how you do the accounting." The answer is also unclear because researchers think that there are many more variable blocks of sequence that are 10,000 or 1,000 letters long and were excluded from the current study. Because of limits with their methods, the new map mainly identified variable chunks larger than 50,000 letters long. Many of these CNVs are thought to be important in our biology. The team found that 10% of human genes are spanned by these regions, meaning that they might be doubled, deleted or otherwise jumbled in a way that could help to determine whether and when we develop diseases. CNVs have already been linked with susceptibility to Alzheimer's disease, kidney disease and HIV, among others, and the new map will help researchers to make connections to other conditions. "There's a general expectation that these things are quite influential," Wigler says. Maps upon maps The new map adds to a whole library of genetic cartography that already points out other landmarks in the human genome. A lot of attention has focused on mapping the places where single letters vary between individuals (single-nucleotide polymorphisms, or SNPs). Other researchers are identifying hard-to-spot regions where a segment can be flipped around so it runs backwards. But there is plenty more for geneticists to navigate and undoubtedly more maps to come. Some will reveal the smaller regions of variation excluded from Hurle's map. Other projects are attempting to mark every single sequence that does something biologically useful, such as making proteins or packaging up DNA into chromosomes. The precise degree to which each person's DNA differs from another may not become clear until geneticists devise a way to read through the entire genome of many different people and compare them all in detail, something that is far too expensive and time consuming today but may become possible with the advent of faster, cheaper sequencing machines. Scherer and his team have already lined up the only two complete human genome sequences produced by the publicly funded Human Genome Project and the private company Celera. They identified both single-letter changes and small and large regions of variation and report their results in Nature Genetics

    (article)
    (ancillary article)
    (study) purty circumstantial, I'd say

    excerpts, selected by me, of course

    ...In contrast to other classes of human genetic variation, the population genetics of copy number variation remains unexplored. The distribution of copy number variation within and among different populations is shaped by mutation, selection and demographic history. A range of polymorphisms, including SNPs25, microsatellites59 and Alu insertion variants60, has been used to investigate population structure. To demonstrate the utility of copy number variation genotypes for population genetic inference we performed population clustering61 on 67 genotyped biallelic CNVs. We obtained the optimal clustering with the assumption of three ancestral populations, with the African, European and Asian populations clearly differentiated (Fig. 7). Population differentiation of individual variants is commonly estimated by the statistic FST, which varies from 0 (undifferentiated) to 1 (population-specific)62. The average FST for the same 67 autosomal CNVs was 0.11, very similar to that observed for all autosomal Phase I HapMap SNPs (0.13)25...

    A triangle plot showing the clustering of 210 unrelated HapMap individuals assuming three ancestral populations (k = 3). The proximity of an individual to each apex of the triangle indicates the proportion of that genome that is estimated to have ancestry in each of the three inferred ancestral populations. The clustering together of most individuals from the same population near a common apex indicates the clear discrimination between populations obtained through this analysis. The clustering was qualitatively similar to that obtained previously with a similar number of biallelic Aluinsertion polymorphisms on different African, European and Asian population samples

    ...Recent population-specific positive selection elevates population differentiation. To explore population differentiation at all CNVs, we devised a statistic, VST, that estimates population differentiation based on the quantitative intensity data and varies from 0 to 1, similar to FST (Supplementary Fig. 16). Estimating VST for all clones on the WGTP array and all CNVs on the 500K EA array revealed a number of outliers with levels of population differentiation suggestive of population-specific selective pressures ...



    Population differentiation, estimated by VST, for each of the three population pairwise comparisons is plotted along each chromosome. For each pairwise comparison, the VST values for all clones on the WGTP platform are shown in the lighter colour with filled circles, with VST values of CNVs detected on the 500K EA platform superimposed in a darker shade with unfilled circles. Histograms showing the distributions of log2 ratios (on the WGTP platform) among the unrelated individuals in each population are plotted for four example CNVs exhibiting high population differentiation, labelled A–D. y axis values indicate absolute frequency. Each example histogram is labelled with the chromosome coordinates of the WGTP clone, and flanking/encompassed genes are given for those CNVs mentioned in the text.


    ...Not all regions that have been under recent positive selection exhibit elevated population differentiation. To detect other CNVs that may have recently been under positive selection, we identified CNVRs that fell within 124 out of 752 (16%) genomic locations previously shown66 to exhibit haplotype patterns suggestive of a partial selective sweep (Supplementary Table 21). Two of these overlapping CNVs also fell within the set exhibiting highest population differentiation, shown in Supplementary Table 20. One of these selection-associated CNVs is a duplication specific to the CEU (Fig. 8) and lies near to the MAPT gene, which is associated with a set of neurodegenerative disorders known as 'tauopathies'67. Both the MAPT gene and the duplication lie within a chromosomal region that has recently been shown to have a complex evolutionary history, characterized by a common chromosomal inversion, deep divergence between inverted haplotypes and recent positive selection in European populations. We adapted methods used to identify partial selective sweeps at SNPs66, 69 to estimate relative extended haplotype homozygosity values (REHH) on either flank of the 67 CNVs for which we extracted genotype information (Supplementary Methods). We identified no convincing signals (P < 0.01 on both flanks) of positive selection on any CNV in any one population, although there were weaker signals (P < 0.05) apparent for some CNVs...



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    Exclamation Each person's genetic makeup differs far more than previously known: study

    Global variation in copy number in the human genome

    Nature 444, 444-454 (23 November 2006)

    Richard Redon et al.


    We obtained the optimal clustering with the assumption of three ancestral populations, with the African, European and Asian populations clearly differentiated

    Copy number variation (CNV) of DNA sequences is functionally significant but has yet to be fully ascertained. We have constructed a first-generation CNV map of the human genome through the study of 270 individuals from four populations with ancestry in Europe, Africa or Asia (the HapMap collection). DNA from these individuals was screened for CNV using two complementary technologies: single-nucleotide polymorphism (SNP) genotyping arrays, and clone-based comparative genomic hybridization. A total of 1,447 copy number variable regions (CNVRs), which can encompass overlapping or adjacent gains or losses, covering 360 megabases (12% of the genome) were identified in these populations. These CNVRs contained hundreds of genes, disease loci, functional elements and segmental duplications. Notably, the CNVRs encompassed more nucleotide content per genome than SNPs, underscoring the importance of CNV in genetic diversity and evolution. The data obtained delineate linkage disequilibrium patterns for many CNVs, and reveal marked variation in copy number among populations. We also demonstrate the utility of this resource for genetic disease studies.
    Link to the article

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    Last edited by Agrippa; Saturday, November 25th, 2006 at 06:53 PM.
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    We're only human? It's more complex than that, says gene study

    New investigations into the code for life suggest the assumption that humans are genetically almost identical is wide of the mark, and the implications could be resounding.

    Current thinking, inspired by the results five years ago from the Human Genome Project, is that the six billion humans alive today are 99.9 percent similar when it comes to genetic content and identity.

    But major research work, published on Thursday, suggests we are genetically more diverse -- and the repercussions could be far-reaching for medical diagnosis, new drugs and the tale of human evolution itself.

    Until now, analysis of the genome has focussed overwhelmingly on comparing flaws, or polymorphisms, in single "letters" in the chemical code for making and sustaining human life.

    An international consortium of scientists has taken a different tack and believe they have uncovered a complex, higher-order variation in the code.

    This better explains why some individuals are vulnerable to certain diseases and respond well to specific drugs, while counterparts swiftly fall sick or never respond to treatment, the authors believe.

    Their focus has been to dig out deletions or duplications of code among relatively long sequences of individual DNA and then compare these so-called copy number variations (CNVs) across a range of volunteers of different ancestry.

    The researchers were astonished to locate 1,447 CNVs in nearly 2,900 genes, or around one eighth of the human genetic code.

    "Each one of us has a unique pattern of gains and losses of complete sections of DNA," said Matthew Hurles of Britain's Wellcome Trust Sanger Institute, one of the project's partners.

    "One of the real surprises of these results was just how much of our DNA varies in copy number. We estimate this to be at least 12 percent of the genome."

    "The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected. We now appreciate the immense contribution of this phenomenon to genetic differences between individuals."

    Some of the missing or duplicated stretches are very long, suggesting that, like backroom switches in a protein factory, CNVs must have a big impact on gene expression.

    Nearly 16 percent of genes that are known to be related to disease have CNVs, the group found.

    These include genes involved in rare genetic disorders such as DiGeorge, Williams-Beuren and Prader-Willi syndromes and those linked with schizophrenia, cataracts, spinal muscular atrophy and atherosclerosis.

    But kidney disease, Parkinson's, Alzheimer's and vulnerability to malaria and the human immunodeficiency virus (HIV), which recent research has blamed on single-letter variations in the gene code, may also well be rooted in CNVs, the doctors believe.

    "The stage is set for global studies to explore anew... the clinical significance of human variation," said Huntington Willard and Kevin Shianna of the Institute for Genome and Science Policy at Duke University in North Carolina, in a review of the research.

    Evolution is another area that will come under new scrutiny.

    The "Out of Africa" scenario, by which Homo sapiens emerged from east Africa and spread around the globe, will not be challenged, though.

    Our origins are so recent that the vast majority of CNVs, around 89 percent, was found to be shared among the 269 people who volunteered blood as samples for the study.

    These individuals included Japanese from Tokyo, Han Chinese from Beijing, Yoruba from Nigeria and Americans of Northern and Western European ancestry.

    All the same, there are widespread differences in CNVs according to the three geographical origins of the samples.

    This implies that, over the last 200,000 years or so, subtle variants have arisen in the genome to allow different populations of humans adapt to their different environments, Wellcome Trust Sanger said in a press release.

    The research, which appears in the British journal Nature, is based on two technical breakthroughs, one in faster, accurate sequencing of DNA and the other in a powerful software programme to spot the CNVs.



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    Each person's genetic makeup differs far more than previously known: study

    Each person's genetic makeup differs far more than previously known: study

    TORONTO (CP) - Scientists have long known that each person on the planet is unique because of individual variations in what is primarily a shared genetic profile. But a groundbreaking new discovery by Canadian-led international researchers has proven these variations are far more extensive than ever anticipated.

    In fact, whole chunks of DNA can differ between individuals, the scientists say.

    The discovery has led to the first map of these genetic variations - and a more sophisticated tool for pinpointing the causes of both rare and common diseases that afflict humankind.

    "We didn't know about this form of variation two years ago," said Dr. Stephen Scherer, director of the Centre for Applied Genomics at the Hospital for Sick Children in Toronto and a co-principal investigator of the research. "And now for the first time we've got a catalogue of information and we've been able to understand the properties of this new type of variation."

    "So then we can really focus our studies and apply this information to genetic disease studies."

    That means scientists around the world now have a new technique to help them home in on the genetic underpinnings of rare inherited diseases as well as those of more common disorders, such as diabetes, heart disease, various cancers, Alzheimer's and Parkinson's.

    What the researchers found, in essence, is that a person's DNA does not contain just two sets of genes, one from each parent, but also on occasion multiple copies of one or more genes and some that are missing altogether. These extra or missing parts of the genome are called "copy number variations," or CNVs.

    The map of CNVs was created after researchers scanned genetic material from 270 people with ancestry from Europe, Africa and Asia. State-of-the-art micro-array machinery allowed them to isolate DNA segments that previous technology was not refined enough to detect.

    While that analysis confirmed that humans share much of the same DNA, it also found that the amount of variation among humans is "huge" - an estimated 12 per cent of any person's genetic material.

    "We found on average about 100 of these large-scale changes in each genome we looked at," said Scherer. "I was really so surprised to see that . . . It was something that we and probably everyone else did not expect."

    The human genome, often dubbed the Book of Life, is made up of about three billion letters (chemical base-pairs called nucleotides). Each of its 30,000 pages (or 30,000 genes) contains about 100,000 letters each. Previously it was believed that genetic variations among individuals occurred because of alterations in single letters that changed the "spelling" of words.

    But the new work shows that variations - whether additions or deletions - affect not only single letters, but also sentences, paragraphs and even whole pages.

    "And now we're seeing in some cases that you get only one page, in some cases you get three, in some cases you get four, and in rare cases you have zero," said Scherer. "Some genes or some pages of the encyclopedia are absolutely missing."

    The research, which involved investigators from Canada, the United States, Europe and Japan, is causing a huge buzz in the scientific community, Dr. Tom Hudson, interim head of the McGill University and Genome Quebec Innovation Centre, said from Montreal.

    "It's very exciting," said Hudson, calling it a "big new step" for medical genetics.

    Different aspects of the research, appear in four papers published this week in Nature and its associated journals.

    "I believe this paper will change forever the field of human genetics," James Lupski, vice-chair of molecular and human genetics at Baylor College of Medicine in Houston, Texas, said in a release.

    Dr. Matthew Hurles of the Wellcome Trust Sanger Institute in Cambridge, England - Scherer's co-principal investigator on one of the papers - agreed that the extent of genetic variation from one person to the next came as a surprise.

    "The copy number variation that researchers had seen before was simply the tip of the iceberg, while the bulk lay submerged, undetected," Hurles said in a statement. "We now appreciate the immense contribution of this phenomenon to genetic differences between individuals."
    http://www.cbc.ca/cp/health/061122/x11229A.html
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    AW: Each person's genetic makeup differs far more than previously known: study

    This implies that, over the last 200,000 years or so, subtle variants have arisen in the genome to allow different populations of humans adapt to their different environments, Wellcome Trust Sanger said in a press release.
    Déjà vu, déjà vu

    "Oh really, are you serious Sir?"

    Well, finally genetics will reach a point from which even politically correct scientists can no longer ignore what physical anthropologists knew very well for quite some time. The gab between classic physical anthropology and genetic research will finally disappear and those "there is no race and there are no real differences, its all just skin deep" nuts will finally be left alone by science in their ideological madhouse. But of course, they will always try to downplay results and play the "politically correct mind police and control-standardised speech" card.

    But again, some idiocies of the past ultra-egalitarian ideologists repeated over and over again are history, just dirt and dust from the past. Its time to correct certain perspectives again...
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