SCHAFER AUTISM REPORT "Healing Autism:

No Finer a Cause on the Planet"

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RESEARCH

* NIH Grant to Support Rural Areas in Helping Children with Autism

* Study: Being Social Keeps Mind Sharp

* Clinical/Neurobehavioural Review Of High-Func.Autism & Asperger's

* Studying Autism and Language Impairment Using Standard

Diagnostic Instruments

* Linkage of Autism With Markers On Chromosome 7

* Entrepenuer Group Seeks Patent Linking Some Milk Proteins And Autism

* Fonterra Says Patent Linking To Autism Is Being Allowed To Lapse

* Gene-Mappers Take New Aim at Diseases

COMMENTARY

* National Alliance for Autism Research's Haplotype Analysis

Cutting Edge Work

*Readers' Posts

RESEARCH

NIH Grant to Support Rural Areas in Helping Children with Autism

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UC Davis Health System’s Center for Health and Technology and MIND Institute have been awarded a $375,000 grant from the National Institute of Mental Health to develop telemedicine as an effective mental health tool for rural communities trying to care for children with autism.

“Since the data suggests that more children are diagnosed with autism in California, it becomes increasingly important for us to use telehealth technologies, such as telemedicine, distance learning and Internet communication, to deliver to rural communities the most effective interventions available to children with this neurodevelopmental disorder," said Thomas S. Nesbitt, associate dean for outreach, telehealth and continuing medical education and director for the Center for Health and Technology. Nesbitt, who is leading this current project, launched the medical center’s first telemedicine project in 1992, linking physicians in sparsely populated Colusa County with obstetrical specialists at the medical center, 70 miles away.

Funding from the grant will bring together a multidisciplinary group of UC Davis experts in sociology, special education, medical ethics, child psychiatry, child psychology, communication sciences and technology and developmental disabilities to assess the effectiveness of telehealth technologies in assisting professionals in rural areas to implement proven treatments for children with autism. Those strategies could encompass procedures for including these children in regular school classrooms, or ways to enhance the children’s learning environment.

“Autism experts are finding that psycho-educational interventions offer children with autism the ability to develop the skills they are missing," said Sally J. Rogers, a UC Davis psychiatry professor and researcher at the MIND Institute. She is also co-principal investigator on the project. “Rural communities often don’t have the specialists or easy access to these kinds of treatments. Through telemedicine, we are hoping to erase the distance so that it would be as if these children lived right next door to the MIND Institute."

The project also will include an advisory board of parents, educators and providers from rural communities who will offer valuable input into the day-to-day challenges of caring for and nurturing these children.

Over the course of the three-year grant, the team will be developing guidelines that address political, legal and ethical issues and will be evaluating different distance learning scenarios, such as individual case management or continuing education opportunities.

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Study: Being Social Keeps Mind Sharp

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New research suggests that just sitting around and chatting with friends may help keep our brains fit enough to fight off mental decline, especially as we age.

Yakking it up with cohorts, it turns out, may keep the mental machinery well oiled.

We've heard for years about what's supposed to happen as we get older. The old brain just doesn't click along at the same speed, the memory begins to fail, and the biggest intellectual challenge of the day may be deciding which channel to watch.

The way to fight that, so we've been told, is to keep the old noggin busy. So millions turn to crossword puzzles, reading and various hobbies, and that's supposed to help.

But to psychologist Oscar Ybarra of the University of Michigan, that picture looked very incomplete.

Mental Gymnastics Ybarra was listening to the radio a few years ago when a report came on about all the things we can do to keep ourselves mentally sharper, like traveling and reading. But as a specialist in social cognition, Ybarra figured there was more to it than that.

"I thought about my grandparents, who lived to be quite old and remained quite lucid," Ybarra says. "They tended to be very active socially, and I thought there was something else going on here."

What was going on, he says, was the "mental gymnastics" that we all go through while interacting socially with others. We do it so often, and with seemingly so little effort, that we're unaware of the fact that just simply socializing requires a strong mental commitment.

"Especially when you're dealing with somebody you're trying to understand," Ybarra says. "You're trying to figure out what motives they have, what beliefs they have. That takes a lot of mental energy."

So Ybarra and colleagues from the University of Michigan and the University of Denver set out to determine if socializing really can help keep the brain in tune. In a new report, they say the answer is a resounding yes. And it doesn't just work for the elderly. They found that regardless of age, people who are more sociable suffer less mental decline than those who avoid social encounters.

"We have provided evidence showing that the degree to which people are socially engaged helps to sustain cognitive functioning," the researchers concluded.

Our brains are "put to use when we do what comes naturally to us — interact with other beings," they argue.

Chicken or the Egg Dilemma The researchers relied on three previous surveys of several thousand persons in the United States and four Middle Eastern countries, Bahrain, Egypt, Jordan and Tunisia. The participants, ranging in age from 24 to 100, were asked a wide range of questions concerning social activities, health, physical activity, and others. Then they were asked to solve problems involving memory and simple arithmetic to assess their mental abilities.

To determine how socially active they were, the participants were asked questions like how often they got together with friends and relatives, how often they talked on the phone, and how many people they knew with whom they could share their intimate feelings.

Regardless of age or nationality or ethnic origin or gender, the results were the same, Ybarra says. Those who were most active socially also showed less mental decline.

"The more participants were socially engaged, the less their cognitive impairment," the researchers concluded.

One could argue that the researchers got it backwards. People who suffered less cognitive impairment remained more socially engaged, so which came first here, the chicken or the egg? Other researchers have found that as people decline mentally, they also tend to withdraw, so it's hard here to pin down the cause and the effect. Perhaps some are socially inactive because of mental decay, and perhaps some suffer from mental decay partly because they are socially inactive.

And Ybarra notes that such things as declining health and loss of income among the elderly can cause both social withdrawal and mental decline, making it more difficult to assess the contributions of social interaction.

Looks Count Participants in the study who were judged to be physically attractive were found to be more socially active, and that's probably because a lot of folks would rather talk with a hunk or beauty queen than a wallflower. The beautiful people also fared better in terms of mental decline, and the researchers think that's attributable at least partly to all that socializing with people who were trying desperately to impress them.

Although the study didn't address this directly, Ybarra suspects that who you are talking to may also make a difference. The mental workout can be more intense, he suggests, if the other person really matters to you.

"Some interactions are going to provide more of a workout than others," he says. "I would think that just greeting the person who delivers the mail may not be as intensive as chatting with a good friend, or actually dealing with a hostile employer."

One problem addressed only indirectly in the study deals with older persons who feel they are no longer taken seriously. That's a common complaint from elders who have to deal with grown children who have decided they can no longer do anything for themselves. Their opinions are rarely sought, and all too often, when they speak, no one listens.

That can lead to one serious result.

"If you don't think you're being taken seriously, you're probably going to withdraw socially," Ybarra says, thus robbing the elderly of the social interaction that might help keep their brains alert.

The system works best, he says, when the conversation matters to both parties.

"That's what provides the framework," Ybarra says, "trying to understand other people's minds."

Lee Dye’s column appears weekly on ABCNEWS.com. A former science writer for the Los Angeles Times , he now lives in Juneau, Alaska.

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Clinical/Neurobehavioural Review Of High-Func.Autism & Asperger's 'A clinical and neurobehavioural review of high-functioning autism and Asperger's disorder.'

ds=12406118&dopt=Abstract

Rinehart NJ, Bradshaw JL, Brereton AV, Tonge BJ.

Objective: To compare, contrast and review clinical and neuropsychological studies of high-functioning autism and Asperger's disorder.

Method: This paper reviews past and contemporary conceptualizations of autism and Asperger's disorder, together with epidemiological information, genetic and neurobehavioural findings.

This paper focuses on neurobehavioural studies, in particular, executive functioning, lateralization, visual-perceptual and motor processing, which have provided an important source of information about the potential neurobiological dissociation that may exist between autism and Asperger's disorder.

Results: The clinical profiles of autism and Asperger's disorder contain a mixture of psychiatric and neurological symptoms: for example, movement abnormalities (i.e.

stereotyped behaviours, hand flapping, toe walking, whole-body movements), atypical processing of parts and wholes, verbal and non-verbal deficits, ritualistic/compulsive behaviour, disturbances in reciprocal social interaction and associated depression and anxiety.

The considerable clinical overlap between autism and Asperger's disorder has led many to question whether Asperger's disorder is merely a mild form of autism, or whether it should be considered as a separate clinical entity.

Conclusion: In light of the growing body of epidemiological information, genetic, and neurobehavioural evidence that distinguishes autism from Asperger's disorder, it is premature to rule out the possibility that these disorders may be clinically, and possibly neurobiologically separate.

PMID: 12406118 [PubMed - as supplied by publisher]

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Studying Autism and Language Impairment Using Standard Diagnostic Instruments 'Exploring the borderlands of autistic disorder and specific language impairment: a study using standardised diagnostic instruments.'

ds=12405479&dopt=Abstract

Bishop DV, Norbury CF.

Department of Experimental Psychology, University of Oxford, UK. dorothy.bishop@psy.ox.ac.uk

Background: Two studies were conducted to test claims that pragmatic language impairment (PLI - previously referred to as semantic-pragmatic

disorder) is simply another term for autistic disorder or pervasive developmental disorder not otherwise specified (PDDNOS).

Method: In Study 1, 21 children aged from 6 to 9 years with language impairments were subdivided on the basis of the Children's Communication Checklist into 13 cases of pragmatic language impairment (PLI) and eight cases of typical specific language impairment (SLI-T).

Parents completed the Autism Diagnostic Interview - Revised (ADI-R) and the Social Communication Questionnaire (SCQ), and the children were given the Autism Diagnostic Observation Schedule - Generic (ADOS-G).

In Study 2, a further 11 children with SLI-T and 18 with PLI were assessed using the SCQ and ADOS-G.

In addition, six children diagnosed with high-functioning autism and 18 normally developing children were assessed.

Results: There was good agreement between ADI-R and SCQ diagnoses, but poor agreement between diagnoses based on these parental report measures and those based on ADOS-G.

In many children, symptom profiles changed with age.

Four PLI children from Study 1 and one from Study 2 met criteria for autistic disorder on both parental report (ADI-R or SCQ) and ADOS-G.

Many of the others showed some autistic features, but there was a subset of children with pragmatic difficulties who were not diagnosed as having autism or PDDNOS by either instrument.

These children tended to use stereotyped language with abnormal intonation/prosody, but they appeared sociable and communicative, had normal nonverbal communication, and showed few abnormalities outside the language/social communication domains.

Conclusions: Presence of pragmatic difficulties in a child with communication problems should prompt the clinician to evaluate autistic symptomatology, but it is dangerous to assume that all children with pragmatic difficulties have autism or PDDNOS.

PMID: 12405479 [PubMed - in process]

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* * *

Theory of Mind in Kids With PDD: A Longitudinal Study.

'Theory of mind in children with 'lesser variants' of autism: a longitudinal study.'

ds=12405477&dopt=Abstract

Serra M, Loth FL, van Geert PL, Hurkens E, Minderaa RB. Academic Centre for Child and Adolescent Psychiatry, The Netherlands.

Background: The study investigated the development of theory-of-mind

(ToM) knowledge in children with lesser variants' of autism (PDD-NOS) over a period thought to be critical for ToM development (i.e., 3 to 5 years of age).

Method: The sample included 11 children with PDD-NOS; 23 normally developing children were included for cross-sectional comparison and 13 normally developing children for longitudinal comparison.

The groups were comparable in verbal and non-verbal mental age.

Two storybooks were used for repeated assessment of various aspects of the children's theory of mind: emotion recognition, the distinction between physical and mental entities, prediction of behaviour and emotions on the basis of desires and prediction of behaviour and emotions on the basis of beliefs.

Results: The results showed that the children with PDD-NOS had specific difficulties in understanding and predicting other people's emotions on the basis of situational cues, desires and beliefs.

However, their ability to predict actions from beliefs and desires were relatively intact.

Compared to the normally developing children, these children achieved lower levels of theory-of-mind knowledge, both at time of initial assessment and approximately 6 months later.

Conclusions: The data suggest that the theory-of-mind development of children with PDD-NOS is both delayed and deviant.

The growth pattem of theory-of-mind skills in children with PDD-NOS seemed to be qualitatively different from the growth pattern found in the group of normally developing children.

PMID: 12405477 [PubMed - in process]

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Linkage of Autism With Markers On Chromosome 7

'Regional meta-analysis of published data supports linkage of autism with markers on chromosome 7'

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2002, Volume 7, Number 1, Pages 56-66

J A Badner and E S Gershon

Department of Psychiatry, University of Chicago, Chicago, IL, USA Correspondence to: J A Badner, MD, PhD, Department of Psychiatry, University of Chicago, 5841 South Maryland Ave, MC3077 Chicago, Illinois 60637, USA.

E-mail: jbadner@yoda.bsd.uchicago.edu

Abstract

Although the concept of meta-analysis of multiple linkage scans of a genetic trait is not new, it can be difficult to apply to published data given the lack of consistency in the presentation of linkage results.

In complex inheritance common diseases, there are many instances where one or two studies meet genome-wide criteria for significant or suggestive linkage but several other studies do not show even nominally significant results with the same region.

One possibility for resolving differences between study results would be to combine an available result parameter of several studies.

We describe here a method of regional meta-analysis, the multiple-scan probability (MSP), which can be used on published results.

It combines the reported P-values of individual studies, after correcting each value for the size of the region containing a minimum P-value.

Analyses of the power of MSP and of its type I error rates are presented.

The type I error rate is at least as low as that for a single genome scan and thus genome-wide significance criteria may be applied.

We also demonstrate appropriate criteria for this type of meta-analysis when the most significant study is included, and when that study is used to define a region of interest and then excluded.

In our simulations, meta-analysis is at least as powerful as pooling data.

Finally, we apply this method of meta-analysis to the evidence for linkage of autism susceptibility loci and demonstrate evidence for a susceptibility locus at 7q. Molecular Psychiatry (2002) 7, 56-66. DOI: 10.1038/sj/mp/4000922

* * *

Fonterra Cooperative Group has registered a patent application for rights to intellectual property showing a connection between milk containing specific proteins and mild autism or asperger's syndrome.

The patent application, published by the World Intellectual Property Organisation on March 14, is for technology to select beta-casein forms of milk for use in foods for individuals genetically susceptible to neurological or mental disorders such as autism.

The patent application, initially filed by the Dairy Board with international publication number WO02/19832 A1, says there is strong analytical and epidemiological evidence to support a relationship between the consumption of beta casein variants and neurological and mental disorders. This is most likely due to the release of the bioactive peptide beta casomorphin 7 (BCM-7)and similar peptides during digestion, according to the application.

But some forms of milk proteins did not trigger the release of BCM-7, it said.

"The consumption of this type of milk will therefore not cause behaviour changes in susceptible individuals."

The patent would cover the selection and supply of milk or milk products which did not trigger autism, to susceptible individuals.

Disclosure of the patent application today by a Fonterra rival, biotechnology company A2 Corporation, follows its unsuccessful efforts recently to persuade Fonterra that it was missing out on a huge marketing opportunity by not adopting milk containing the A2 protein – for which A2 Corp already controls some intellectual property.

A2 Corp was formed in early 2000 to exploit commercial opportunities from initial studies indicating that a milk protein, beta casein A1, causes diabetes and heart disease. It has commissioned trials at Brisbane on rabbits, comparing the effects of diets of A1 and A2 proteins, and expects other, separate, human trials of the A1 protein in Melbourne to be completed by year end.

A2 Corp chief executive Corran McLachlan said last month he believed Fonterra was missing out on a top marketing opportunity.

"We have got Southeast Asian supermarket chains who would buy all the A2 milk we can supply – their main concern is that people will totally switch off ordinary milk unless they can get A2," he said.

But instead Fonterra responded with a cautionary rebuke that its own analysis in the mid-1990s did not support the link claimed by Dr McLachlan between milk containing A1 protein and heart disease, and urged consumers to be cautious about the latest research findings.

Dr McLachlan has previously estimated about a third of New Zealand's dairy cow herd carried the A2 protein and said the country's milk consumption could eventually be made entirely A2-based. At present, about 80 per cent of cows produce milk containing A1 proteins.

A2 Corp would earn revenue from diagnostic testing for A1 protein, and from royalties and licensing fees related to its patents, which include a method of producing pure A2 milk.

But today, Dr McLachlan said A2 Corp plans to take action in the High Court at Auckland against Fonterra.

"We have filed a High Court action," he said. He declined to comment at this stage on the grounds of the action, which a court official confirmed had been set down for a preliminary conference before a duty judge on December 10.

Dr McLachlan said Fonterra's patent application over the selection of A2 milk to avoid the release of brain chemicals which might induce or aggravate neurological or mental disorders had linked deaths from mental illness with the consumption of A1 milk.

And a legal spokesman to whom he referred NZPA, said: "The directors of A2 Corporation believe that particularly in light of the recent disclosure of applications for patent, in respect of autism and other neurological disorders, that the duty of Fonterra towards its customers needs to be explored."

The filing of a High Court action by A2 Corp effectively raises the stakes in an increasingly antagonistic battle with Fonterra over health claims related to milk proteins.

Dr McLachlan has said if there was an effort to cull and breed out the A1 protein from the national herd the process would take a couple of years.

A2 Corp's origins date back to 1994 when the Child Health Foundation asked Dr McLachlan, a chemical engineer, to review the University of Auckland's medical school research on the link between milk and Type 1 diabetes.

The school observed that Samoan children who emigrated to New Zealand developed diabetes at much higher levels than they did in Samoa, and that a major addition to their diets, once in New Zealand, was cow's milk.

It was also observed that African Masai children didn't develop diabetes despite drinking lots of cow's milk – the difference being that the Masai have cattle producing milk that contains beta casein A2, while milk from New Zealand cows contains a mixture of beta casein A1 and A2.

The Auckland University team filed a patent, now jointly owned by A2 Corp and Fonterra, which is recognised in New Zealand and Australia and is pending in Europe, USA, Canada, Finland and Norway. Fonterra assumed ownership of half the patent as a result of last year's dairy industry merger.

Dr McLachlan said last month that A2 Corp was going to need more capital in the near future and might sell part of its wholly owned European or USA operations to raise funds.

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Fonterra Says Patent Linking To Autism Is Being Allowed To Lapse

Fonterra Cooperative Group says new scientific work has failed to substantiate the research on which it based a patent application linking milk containing specific (A1) proteins with mild autism or asperger's syndrome.

Most New Zealand milk contains a mix of A1 and A2 proteins.

Fonterra's director of corporate research and development, Chris Mallett, said today the company had allowed the patent to lapse, even though it was made publicly available only in March.

He said the patent had been taken out, largely based on epidemiological studies, as a commercial precaution in case further research revealed a useful discovery.

In the early stages of work related to the research, a memo on it, written in October 2000, by dairy research scientist Jeremy Hill, "was given to a major shareholder of A2 Corp by a senior executive of the New Zealand Dairy Board," Dr Mallett said.

A2 Corp is a biotechnology company which has said it shortly hopes to launch a brand of milk in New Zealand without A1 proteins.

Much of that memo was today published in the National Business Review newspaper, under a headline saying: "Secret memo reveals Fonterra alarm".

But Dr Mallet said Dr Hill had warned in the memo: "If the media (or A2 Corporation) were ever able to assemble the information shown in this paper, they could put an alarmist spin on the whole area of milk consumption, or alternatively leap to conclusions about A1 versus A2 effects, before a case is proven either way."

Today he said the application of the patent had been overtaken by subsequent research.

"There is no scientific evidence, currently available to Fonterra, published or otherwise, which indicates that A1 milk causes any of the negative health effects claimed by A2 Corporation," he said.

The patent application, published by the World Intellectual Property Organisation on March 14, was for technology to select beta-casein forms of milk for use in foods for individuals genetically susceptible to neurological or mental disorders such as autism.

The patent application said there was strong analytical and epidemiological evidence to support a relationship between the consumption of beta casein variants and neurological and mental disorders.

This was most likely due to the release of the bioactive peptide beta casomorphin 7 (BCM-7) and similar peptides during digestion, according to the application.

But some forms of milk proteins did not trigger the release of BCM-7, it said.

"The consumption of this type of milk will therefore not cause behaviour changes in susceptible individuals."

The patent was to cover the selection and supply of milk or milk products that did not trigger autism, to susceptible consumers.

The publication of the patent application was publicised today by A2 Corporation, following its unsuccessful efforts recently to persuade Fonterra that it was missing out on a huge marketing opportunity by not adopting milk containing the A2 protein - for which A2 Corp already controls some intellectual property.

But Dr Mallett said subsequent research had reinforced Fonterra's view that science did not back A2 Corp's claims.

"In the absence of supporting scientific evidence and given the many proven health benefits of dairy products these claims about milk are irresponsible," he said.

If Fonterra had become aware in any of the follow-up research of any scientifically-proven health issues, it would have immediately alerted consumers, Dr Mallett told NZPA.

"Fonterra is an ethical company and it operates always in the best interests of its customers and consumers," Dr Mallett said.

"If there are questions raised about milk, we do our best to look at them and track them down."

The autism work had been in the public domain even before the 1999 publication of two novel animal studies which indicated some cases of autism and schizophrenia might be linked to an individual's inability to properly break down a protein found in milk.

University of Florida physiologist Robert Cade said at the time the digestive problem might actually lead to the disorder's symptoms. When not broken down, the milk protein produced exorphins, morphine-like compounds that are then taken up by areas of the brain known to be involved in autism and schizophrenia, where they cause cells to dysfunction.

Dr Cade said a high proportion of autistic and schizophrenic children studied had 100 times the normal levels of the milk protein in their blood and urine. When these children were put on a milk-free diet, at least eight out of 10 no longer had symptoms of autism or schizophrenia.

In Dr Cade's studies, researchers injected rats with the protein beta casomorphin 7 (BCM-7) one of the key constituents of milk and the part that coagulates to make cheese.

They then observed their behaviour and later examined brain tissue to see whether the substances accumulated there.

Beta casomorphin 7 was taken up by 32 different areas of the brain, Dr Cade said, including sections responsible for vision, hearing and communication.

"This could explain several of the things one sees in autism and schizophrenia, such as hallucinations," he suggested.

But Bennett Leventhal, professor of psychiatry and paediatrics and director of child adolescent psychiatry at the University of Chicago School of Medicine, said at the time other studies exploring a dietary link to autism or schizophrenia had been less than convincing, and the notion had not generally been accepted in the field.

Dr Mallett said the New Zealand dairy industry's initial empidemiological work showed there might be a link between A1 casein and symptoms of autism.

So, while it sought a patent to protect any potential commercial value, it conducted animal and human trials in New Zealand. "We haven't published them because the results have been ... they haven't given any results," he said.

Because of this lack of substantiation Fonterra was allowing the provisional patent to lapse.

"There is no confirmed evidence of A1 causing autism," he said. Autism is a cluster of diseases and usually diagnosed from the patients' symptoms, which typically appear during the first three years of life and are characterised by problems interacting and communicating with others.

* * *

Gene-Mappers Take New Aim at Diseases

A $100 million project to develop a new kind of map of the human genome was announced today by an international consortium. Its goal is to hasten discovery of the variant genes thought to underlie common human diseases like diabetes, asthma and cancer.

The consortium includes government agencies from Japan, China and Canada, and a medical charity, the Wellcome Trust of London. Its largest contributor, from the United States, is the National Institutes of Health, which is investing $39 million over the project's three years.

The map will be constructed by analyzing the genomes of people in four ethnic groups: Japanese, Chinese, the Yoruba people of Nigeria, and Americans of Northern and Western European descent. If these four groups do not capture a thorough enough pattern of human variation, more may be added later.

The principle underlying the map is a discovery about the human genome made only a year ago by Dr. Mark J. Daly and colleagues at the Whitehead Institute in Cambridge, Mass. They found that human DNA has been inherited generation after generation in large, unchanged blocks, up to 100,000 units in length, from the ancestral human population and, contrary to what had been assumed, has not yet been thoroughly mixed by the vigorous shuffling of DNA from the maternal and paternal chromosomes that takes place between generations.

These large blocks of DNA are known as haplotypes, and the new map, called the International HapMap, will chart the location of these blocks throughout the human genome. Dr. Eric Lander, Dr. David Altshuler and other members of the Whitehead Institute have rapidly expanded on Dr. Daly's discovery, and the N.I.H. has boldly built the hapmap project around it.

Dr. Francis Collins, director of the genome institute at the N.I.H., said today that the undertaking was virtually certain to be successful. He described it as a project that "will provide a critical missing link to allow researchers all over the world to uncover the hereditary factors in common disease and behind the response to drug therapy."

But in part because the discovery is so new, other population geneticists do not yet agree on the nature or the extent of the haplotypes in the human genome, and some doubt that the hapmap approach will be very useful in tracking down the variant genes that cause common diseases.

"I have some major reservations," said Dr. Kenneth Kidd, a population geneticist at Yale. "I'm not opposed to going ahead, but a smaller-scale effort would probably be better. When there are fundamental basic science questions, a factorylike approach is not the best way."

Dr. Kenneth Weiss, a population geneticist at Pennsylvania State University, said he was "skeptical about the chance the hapmap will satisfy the objectives of identifying common major disease variants."

And Dr. Kari Stefansson, chief executive of Decode Genetics of Reykjavik, Iceland, said he thought the hapmap would be an inefficient way of finding disease genes. Dr. Stefansson said his company had identified seven common disease genes and found the location in the genome of 25 others by studying patients in Icelandic genealogies. In his view, the hapmap approach "isn't useless, but this is not the most effective way of doing what they want to do."

The goal of the hapmap is not to find disease genes directly but to create a general tool that will allow others to do so. It is designed to work in general populations and does not require patients to be related to one another, unlike the basis of the Decode approach in Iceland.

The $3 billion human genome project provided the sequence of a single genome but did not catalog the variations that are thought to underlie many common diseases. The genome sequence was expected to speed the search for such variations, but in practice they have proved much harder to find than expected.

The disappointment has been all the greater because of the success scientists have had in identifying the cause of diseases that proceed from a single gene, such as cystic fibrosis; most of these diseases are quite rare.

Unlike the single-gene diseases, most common diseases are thought to be caused by several variant genes acting together. Because each contributory gene has a weak effect, none stands out.

Since 1996, geneticists have hoped to track disease genes by establishing a SNP map. SNP's (pronounced snips) are the sites of common single base variations in the human genome. With a set of SNP's spread out across the genome, it should be possible to see where in the SNP field the patients differ from people free of a disease, and thus to pinpoint the genetic changes at the disease's root.

But some 500,000 SNP sites across the genome are needed to make the process work, and given the cost of detecting each SNP — some 30 cents — the price of charting each person's SNP map became prohibitive.

That gloomy picture seemed to change when Dr. Daly and his colleagues, looking for the genetic cause of Crohn's disease, an inflammation of the bowel, found that large blocks of SNP's stayed together between the generations and seemed to have been inherited more or less unchanged from the ancestral human population. The swapping of genetic material seems to occur at special hot spots along the chromosome, leaving the material in between pretty much unshuffled.

Since SNP's are inherited in blocks, or haplotypes, the Whitehead scientists soon figured out that it should be possible to define a block by identifying just a few of its SNP's. If a haplotype map of the human genome could be constructed, then the genomes of patients and control groups could be compared block by block, helping to identify the block in which a disease-causing gene resides. Present data suggest that each block comes in three or four versions in the human population, said Dr. Altshuler, of the Whitehead Institute.

Dr. Collins, of the N.I.H., said the hapmap would provide "a powerful and elegant shortcut" to locating disease genes.

Though most geneticists believe that the hapmap will be useful to some degree, there is a range of expectations. Dr. Collins said his guess was that "well over 60 percent of the genes in common disease will be amenable to this approach."

But some experts feel that less than 60 percent of the genome exists in haplotypes. Further reducing the hapmap's reach, the haplotype approach is likely to find only the disease-causing variant genes that are reasonably common in the population. Some geneticists argue that most disease-causing variants are in fact rare, and will not be picked up by the hapmap.

Because of these possibly severe constraints, several geneticists voiced suspicion that the project's ulterior purpose was to provide work for the big genome centers, like that of the Whitehead Institute, now that the human genome project is nearly finished.

Dr. Collins, however, said that "I completely reject the idea that this is a make-work project for the genome centers."

* * *

COMMENTARY

National Alliance for Autism Research's Haplotype Analysis Cutting Edge Work

[The following is a NAAR Commentary and does not necessarily reflect the views of the Schafer Autism Report.]

(See preceding reprint of article.)

The article focuses on a new initiative that utilizes the cutting edge genetics technology known as haplotype analysis to help researchers locate disease susceptibility genes. Specifically, the story reports on a new $100 million project to develop a new type of map of the human genome that was recently unveiled by an international consortium composed of government agencies from the U.S., Japan, China and Canada, and a medical charity in Britain.

The National Alliance for Autism Research (NAAR) finds itself ahead of the curve in developing research excellence. The collaborative genetics initiative funded by NAAR earlier this year, which features Dr. David Skuse and Dr. Eric Lander (Dr. Lander is named in the New York Times article) is utilizing the haplotype analysis technology reported in the Times article. Dr. Skuse and Dr. Lander are exploring the genetic relationship between Turner Syndrome and autism and plan to map specific regions of the genome in the hopes of locating susceptibility genes for a common symptom of autism and Turner Syndrome: the inability to recognize fear as a facial expression. This project marks one of the first times that haplotype analysis is being used to explore the genetics of a psychiatric condition.

It is encouraging to see the media showing interest in this unique topic. National Public Radio also featured it in today’s broadcasts.

Please note that some of the criticisms cited in the New York Times article can be addressed by the approach many NAAR-funded genetic researchers are taking with regards to current and upcoming genetic research projects. They benefit from a combination of cutting-edge population level haplotype analysis technology pioneered at the Whitehead Institute at MIT and more traditional linkage-type analysis involving family pedigrees.

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