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Our Thanksgiving: Each person’s genetic makeup differs far more than previously known: study

Racists Proven Right … Again!

It was nice while it lasted. But the idea that all the world’s people are 99.9 per cent genetically identical — that a mere sliver of DNA separates a Dolly Parton from a Dalai Lama — is untrue.

Their research finds that the size of at least 12 per cent of the genome — including 2,900 genes and regions between them — can differ dramatically between people, and in some cases, between certain ethnic groups.

See, also: Related story

Study turns human genetics on its head

Research finds abnormal is really normal, puts in question some medical tests

CAROLYN ABRAHAM

From Thursday’s Globe and Mail

It was nice while it lasted. But the idea that all the world’s people are 99.9 per cent genetically identical — that a mere sliver of DNA separates a Dolly Parton from a Dalai Lama — is untrue.An international research team has overturned the harmonious message that flowed from the Human Genome Project in 2000 and discovered more DNA differences exist among people than the experts expected.

Using new technology to study the genomes of 270 volunteers from four corners of the world, researchers have found that while people do indeed inherit one chromosome from each parent, they do not necessarily inherit one gene from mom and another from dad.

One parent can pass down to a child three or more copies of a single gene. In some cases, people can inherit as many as eight or 10 copies.

In rare instances a person might be missing a gene.

Yet despite these anomalies, they still appear to be healthy — countering the notion of what doctors have deemed “normal” in genetics.

The work highlights how DNA helps to make each human unique, hinting that a towering basketball player, for example, might boast extra copies of a growth gene or that a daughter really might be more like her dad.

But the landmark report, published today by the journal Nature, also has disturbing implications.

It suggests that some medical tests –such as prenatal scans — may have incorrectly flagged these kinds of genetic quirks as signs of potential defects).

However, it also makes clear that scientists have missed clues to the kinds of genetic traits that can underpin disease.

“The genome is like an accordion that can stretch or shrink . . . so you have no idea what’s normal,” said Steve Scherer, a senior scientist at the Hospital for Sick Children in Toronto and study co-author.

Even the number of genes people can inherit, he said, a premise set out 150 years ago by Austrian monk Gregor Mendel, the father of modern genetics, has been upended.

“We have to think of genetics in an entirely different way. We’re actually more like a patchwork of genetic code than bar codes that line up evenly,” Dr. Scherer said. “Everything we’ve been taught is different now.”

The Sick Kids team worked on the project for more than two years with scientists at Harvard Medical School, the Wellcome Trust Sanger Institute in England, the University of Tokyo and the California-based Affymetrix Corp.

Their research finds that the size of at least 12 per cent of the genome — including 2,900 genes and regions between them — can differ dramatically between people, and in some cases, between certain ethnic groups.

The size differences are the result of DNA that is either duplicated or deleted or contains unexpected added bits of genetic code. Scientists call the phenomenon “copy number variation” or CNV for short. And it is already reshaping genetic research.

“When we’re accounting for what the human genome means, there’s not going to be a single human genome map that is going to be useful to one person,” said Robert Hegele, a noted genetic scientist at the Robarts Research Institute in London, Ont., who read the study. “It’s a huge surprise that there’s so much variation of this type . . . that is so common in so many healthy people.”

For this reason, scientists agree that doctors looking at less-detailed genetic tests — such as karyotyping — might have mistaken unusually-sized bits of DNA as signs of a medical problem.

Patients, or prospective parents receiving results of a prenatal test, for instance, might have been informed that something looked abnormal when, the new work suggests, it isn’t.

While the report does not delve into the issue directly, Dr. Scherer acknowledged this is a possibility. He offered as an example a genetic test that relies on a “diagnostic probe” to evaluate the length of DNA code near the ends of chromosomes.

Shorter chromosomes, he said, are implicated in developmental delay or mental retardation due to DNA code that might be missing.

“But we found that in a large number of cases (shorter chromosomes) exist in the general population,” said Dr. Scherer, who is also director of the Centre for Applied Genomics. “The chromosomes don’t necessarily line up evenly . . . so people really need to scrutinize these results more closely before assuming it’s pathogenic.

“The bottom line is that there’s so much natural variation you have to go back and look closer.”

Dr. Hegele agreed that such things might have been misread. “It’s always been assumed those big changes would result in some type of disease, that they were rare and would lead to sort of catastrophic conditions,” he said, noting that Down syndrome is the result of an extra copy of chromosome 21.

“But you’re always dealing with clinical uncertainties and the best knowledge that’s available at the time.”

Human DNA is a chemical code of roughly three billion letters. These letters, A, C, G and T, are nucleotides that can spell out the recipe for a gene. Previously, scientists have paid almost exclusive attention to mutations that involved a single letter change in the recipe — an A, where others carry a T — a so-called SNiP. But the new report shows that a gene recipe, like any recipe, can also change if quantities of an ingredient are much larger or missing.

Dr. Hegele, an endocrinologist who has been studying the genes of patients with a family history of high cholesterol said, “We assume there are normal numbers of copies [of genes] there when we’re looking at their code. But in fact, it could be that one [gene] is totally missing.”

Scientists suspect that evolutionary pressures likely triggered some genes and DNA regions to increase in one part of the world, yet wither in another.

The international consortium found that a gene already known to be involved in HIV susceptibility, for example, is carried in higher numbers in the DNA samples from Africa, where HIV rates dwarf those in other parts of the world.

In total, the report found that about 15 per cent of the 2,000 disease-related genes known can be affected by such a variation.

Researchers conducted the study using the 270 DNA samples and health information that had been collected for the Haplotype Map. That map, completed last fall, was the first catalogue of common genetic differences — SNiPs — between four major ethnic groups, the Han Chinese, the Japanese, U.S. citizens of European descent and the Yoruba tribe of Nigeria.

The Haplotype Map, like the 2000 Human Genome Map, suggested there were few differences between these groups of people, with only rare examples of mutations that appeared only in one population.

The new work suggests the differences could be slightly more pronounced, largely because researchers had access to new technology that changed the vantage point of the genome.

Using a microchip developed by Affymetrix, Dr. Scherer explained that they were able to view the genome in chunks as small as 1,000 nucleotides, but still be able to pull back and see as many as five million. He compared it to a telescope that allows you to home in and see a single sun and its neighbouring planet, but that also has to the power to zoom out and reveal the wider solar system and “find out there are two suns.”

Tom Hudson, who led Canada’s contribution to the Haplotype Map, applauded the new work, calling it a “a tool that will be immediately useful.” He said he is using it to reanalyze the genomes of 1,200 people with colon cancer and compare them to 1,200 people without it.

“In the early years it’s going to be hard to interpret,” said Dr. Hudson, who is also the scientific director of the Ontario Institute for Cancer Research. “We are going to see things and want to conclude that this is possibly what makes people sick, but it may not be.”

Glossary of genetics

The human genome: All of the genetic information carried inside a cell.

DNA: Deoxyribonucleic acid is the chemical code that provides the genetic instructions to build and operate a human being. It is wound like a spiralling ladder into the 23 pairs of chromosomes found in the nucleus of our cells. There are about three billion rungs on the ladder.

Chromosomes: The rod-shaped structures inside our cells made up of DNA.

They house genes along their length like box cars on a train. People inherit 46 chromosomes from their parents, 23 from the mother and 23 from the father.

Genes: The essential units of heredity. Each gene encodes a recipe to make a protein and proteins make the stuff that help to make us human — lips, liver, the frontal lobes of our brains.

Humans carry about 30,000 genes. They make up only about 3 per cent of the genome. It was thought people inherit only two copies of a gene, one from each parent. But the new work shows this can vary. A person can, in some cases, inherit as many as 10 copies or none at all.

Nucleotides: These chemicals are the building blocks of DNA. They are represented by the letters A, C, G and T — A stands for adenine, C for cytosine, G for guanine and T for thymine. One letter is found at the end of each rung on the ladder that makes up DNA. This way A joins to T and C to G. The partnering is called a base pair.

The letters, or nucleotides, can combine to spell out the recipe for a gene, or a protein.

Junk DNA: This refers to the 97 per cent of genetic code in DNA that does not encode the recipe for a gene. These long stretches of code are now thought to be linked to regulating genes.

SNiPs: The mutation type best known in human DNA. It stands for “single nucleotide polymorphism” and refers to a single-letter change in the DNA code, a T where others carry a C, for example.

— Carolyn Abraham

http://www.theglobeandmail.com/servlet/story/RTGAM.20061123.wxgenome23/BNStory/specialScienceandHealth/home

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The Diversity of Mankind

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

Published: Wednesday, November 22, 2006 | 6:27 PM ET

Canadian Press: SHERYL UBELACKER

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