Foundations of Genetic Algorithms

First, current gene tests cannot provide a satisfactory answer for everyone who seems to be at risk for inherited breast or colon cancer. In some families, multiple cases may reflect shared environmental exposures rather than inherited susceptibility. Even when an inherited gene is to blame, it is not necessarily the test gene; the BRCA1 gene mutation, for example, is found in only about half of the families with hereditary breast cancer.

Second, despite major advances in DNA technology, identifying mutations remains a great challenge. Many of the genes of greatest interest to researchers are enormous, containing many thousands of bases. Mutations can occur anywhere, and searching through long stretches of DNA is difficult.

In addition, a single gene can have numerous mutations, not all of them equally influential. The cystic fibrosis gene, for instance, can display any one of more than 300 different mutations, which cause varying degrees of disease; some seem to cause no symptoms at all. Thus, a positive test does not guarantee that disease is imminent, while a negative test - since it evaluates only the more common mutations - cannot completely rule it out.

Furthermore, predictive tests deal in probabilities, not certainties. One person with a given gene, even one that is dominant like the hereditary breast cancer gene, may develop disease, while another person remains healthy, and no one yet knows why. A gene may respond to the commands of other genes or be switched on by an environmental factor such as sunlight.

Perhaps the most important limitation of gene testing is that test information often is not matched by state-of-the-art diagnostics and therapies. Many diseases and many types of cancer still lack optimal screening procedures; it is often not possible to detect an early cancer even in an individual with a known predisposition.

In inherited breast cancer, frequent screening with mammography offers the best chance of early detection, but falls short of prevention. Moreover, mammography is least effective in the glandular breasts of young women, the very ones at greatest risk from an inherited susceptibility. For the moment, the best assurance of prevention may lie in drastic and costly surgery to remove the breasts - but even a total mastectomy can leave some breast cells behind. As for the ovarian cancer that threatens high-risk families, available screening measures often cannot discover disease in time. Here, too, women in high-risk families often opt for prophylactic surgery to remove the ovaries. To date, however, neither type of prophylactic surgery has been proven to prevent completely the occurrence of cancer.

Scientists are actively studying interventions aimed at the prevention of cancer. For example, ongoing clinical trials are evaluating the use of tamoxifen, an anticancer drug, as a breast cancer preventive. However, such approaches are still in the realm of research.

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What are the risks of gene testing?
The physical risks of the gene test itself - usually no more than giving a blood sample - are minimal. Any potential risks have more to do with the way the results of the test might change a person’s life.

Psychological impact. First, there are the emotions aroused by learning that one is - or is not - likely to develop a serious disease. Many people in disease families have already seen close relatives fall victim to the disorder. The news that they do indeed carry the disease gene can elicit depression, even despair.

Few studies to date have looked directly at the outcome of gene testing for cancer. One study found that, after 3 to 6 weeks, the women identified as gene carriers experienced persistent worries, depression, confusion, and sleep disturbance. Even half of the noncarriers reported that they continued to worry about their risk status.

A gene test confirming the risk of a serious disease
can trigger profound psychological consequences.

Family relations. Unlike other medical tests, gene tests reveal information not only about ourselves but about our relatives, and the decision to have a gene test, as well as the test results, can reverberate throughout the family. If a baby tests positive for sickle-cell trait, for example, it follows that one of his or her parents is a carrier. It is also possible for gene tests to inadvertently disclose family secrets involving paternity or adoption.

Emotions elicited by test results can produce a shift in family dynamics. Someone identified as carrying the gene may feel anger, while one who has escaped may be overwhelmed by guilt for avoiding a disease that afflicts a close relative.

Family issues are especially prominent in research programs where genetic linkage tests depend on testing many members of the same family. Some family members may not want to participate in the study or know their genetic risks. People considering gene tests may want to find out how their relatives would feel about knowing whether or not they have a disease gene or allowing the information to be given to others.

Someone who elects to have a gene test needs to consider whether or not to share the test results with other members of the family. Do they want to know? Who should be told - spouse, children, parents, fiancŽ? Should someone in a high-risk family be tested before she or he marries? What will a positive test mean to one’s relationships? If one chooses not to learn the results of the family’s gene testing, can such a request be respected? How?

The question and issues raised by gene testing
can challenge family and other personal relationships.

Medical choices. Someone who tests positive for a cancer susceptibility gene may opt for preventive or therapeutic measures that have serious long-term implications and are potentially dangerous or of unproven value. In the first family to be tested for a BRCA1 mutation, for instance, some women chose surgery to remove their breasts - and ovaries, too, after childbearing was completed. Other families told the genetic counselor that they were not interested in even discussing surgery.

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2. Prenatal During pregnancy, there are tests that can be done to determine whether or not the fetus has a chromosome abnormality, certain single gene disorders or structural abnormalities. Women who might benefit from prenatal diagnostic tests and counseling include the following: * Women who will be 35 years old or older at delivery * A woman and/or her partner who are known to carry genes coding for a genetic disorder * A woman or her partner who are known to carry a chromosome rearrangement or abnormality * Couples with a family history of a neural tube defect * Couples with a previous child born with multiple congenital anomalies or a chromosome abnormality * Women with an abnormal level of maternal serum alpha fetoprotein (AFP), human chorionic gonadotrophin (hCG), or estriol (uE3) * Women exposed to an infectious disease, radiation, drugs or other environmental agents during pregnancy Due to the increased risk of chromosome abnormalities in babies born to women over the age of 34, the American College of Obstetricians and Gynecologists recommends that all pregnant women who will be 35 years or older at delivery should be offered the option of prenatal diagnosis. The College also recommends that a maternal serum marker screen be offered to all pregnant women between 15 and 18 weeks gestation. Many single gene disorders can be diagnosed prenatally. As the technology is changing rapidly, if the patient or her partner has a single gene disorder or if they have a child with a recessive genetic condition, it is important to determine if new prenatal tests have been developed since the last pregnancy. Women who are exposed to teratogenic agents during pregnancy may also benefit from genetic counseling. In some instances the risk of an abnormality may be much lower than first assumed and counseling may reduce maternal anxiety. In some cases, further diagnostic studies may be proposed to assess fetal development or to rule out the presence of obvious structural defects associated with exposure to a specific agent. Only rarely are the risks of a birth defect high enough to make pregnancy termination a reasonable option.

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When people hear the word “genetics” they often think of pregnant women, children with birth defects, and childbearing couples. This term rarely conjures up thoughts of healthy adolescents or adults. Therefore, you may not readily recognize everyone who might benefit from a genetic consultation.

While there are no established criteria for the types of patients that merit genetic consultation, there are some general rules you can use. The following is a list of reasons for referral. This list has been divided into the different stages in the life cycle.

1. Preconception
Prior to conception there are a number of factors that might lead you to conclude a woman/couple could benefit from a consultation. The reasons for referral include the following:

* A positive family history of a genetic disorder (e.g., fragile X syndrome, muscular dystrophy, cystic fibrosis) and concern about recurrence
* Members of a high-risk ethnic group
* Previous infertility or sterility problem
* Exposure to potential teratogenic or mutagenic agents
* Maternal health (e.g., diabetes, PKU, epilepsy)
* Consanguineous marriage
* Anxieties over childbearing
* Two or more prior miscarriages or pregnancy losses
* A previous stillborn child
* A previous child with a genetic or chromosomal disorder or birth defect (e.g., neural tube defect, Down syndrome, PKU)

The goal of preconception counseling is to provide couples with the information necessary to make informed decisions about reproduction and the available testing, intervention or treatment options. Members of high-risk ethnic groups, for instance, should be told that carrier testing is available. Individuals who carry a balanced chromosome rearrangement should be offered the option of prenatal diagnosis in future pregnancies, and women who are using teratogenic agents should be counseled about the associated risks.

The advantage of preconception counseling is that it is possible to pursue genetic studies prior to pregnancy. In the absence of time constraints, a tiered evaluation can be done. Medical records can be requested and reviewed, laboratory tests can be ordered and analyzed systematically, and extended family studies can be undertaken as needed.

Other reasons to pursue genetic studies prior to conception include the fact that some test results are unreliable during pregnancy (e.g., hexosaminidase enzyme levels in pregnant women who carry the gene for Tay-Sachs disease). Certain prevention strategies may only be effective if instigated prior to conception. For instance, all women of childbearing age should take 0.4 mg of folic acid daily to decrease the risk of having a child with a neural tube defect. Women who have had an affected child should take 4 mg of folic acid daily for three months prior to conception. This has been shown to significantly decrease the recurrence of NTDs in subsequent pregnancies.

Women with health problems are more likely to have babies with birth defects. For example, babies born to insulin dependent diabetic women are more likely to have congenital heart defects, genitourinary defects, and caudal regression sequence, unless the diabetes is strictly controlled prior to conception and during the first trimester. Mothers with PKU need to have normalized levels of phenylalanine prior to conception to prevent mental retardation in the child. Women on anticonvulsant medication should be switched to the least teratogenic drug, and the smallest clinically effective dose.

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How interesting that the Association of British Insurers should announce an extension to the moratorium on predictive genetic test result disclosure, extending it to 2014.

That’s great news indeed, except of course, that the insurance companies will simply use other ways to get round the freeze and will continue to penalise those who test positive for any condition.

The news release they issued on 13 June reads:

“The ABI (Association of British Insurers) has today announced that the moratorium enabling consumers to take out substantial amounts of insurance without having to disclose adverse results of predictive genetic tests has been extended to 2014.

Stephen Haddrill, the ABI’s Director General, said:
“The moratorium on the use of predictive genetic test results works well for consumers. It means people can insure themselves and their families, even if they have had an adverse result from a predictive genetic test. The moratorium has proved effective since its introduction in 2001 and can now continue.”

What a pity then, that some insurers ignore the moratorium and that some GP’s feel obliged to divulge the information when they are completing the health questionnaires from the insurance companies.

Of course, the insurer’s have to pay GP’s to complete the forms. Some then pass the form to a junior who actually answers the questions, but probably doesn’t understand the fact that don’t have to divulge the genetic test results.

Make no mistake, if you submit yourself for genetic testing, you could be in a for some heavy penalties when you come to take out life insurance.

I know. I’m struggling with this very issue right now.

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From Bringing Home the Birkin by Michael Tonello:

Pink-and-green flowered tiles accented the mostly white floor, with the same floral design mirrored in the quilt. The pair of overstuffed chairs and couch were all pink to match, and my masculinity was momentarily threatened until I remembered I was gay. My Y chromosome was further comforted by the dark mahogany furniture and ceiling fans, as well as the gender neutral white walls.

Update: For more, see Christina’s book review at eBeautyDaily.

Tags: Birkin, book, Bringing, ceiling, Christina, couch, design, DNA, Excerpt, floor, furniture, gender, mahogany, Michael Tonello, pair, pink, Pink-and-green, quilt, review, Update

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Andrew Yates of Think Gene is feeling blunt today as he tells us what DNA means to him.

Nothing.

My background is computer science, so to me, DNA is the object code of life. Unlike human-designed languages, DNA is entirely unbounded by intelligibility or elegance —only function.

So we are looking for meaning at the wrong level of abstraction. Our understanding of DNA is tainted by an anthropomorphic misunderstanding of how a language “should” work: “genes” are “sequences of letters” positioned by an “index” like words in a book. One word, one meaning[1]. This is a mistake, as supported by the inconsistent success of genome-wide association studies (GWAS) and the disappointing usefulness of today’s genomic testing.

We don’t try to understand object code in software without abstraction, so why do we try to understand DNA directly in life? Here’s why we shouldn’t try to understand DNA directly —even more so than object code:

* DNA is an implementation, not a map of abstractions. That is, units of DNA have no constraint to “mean” anything. Even object code can usually be interpreted as processor instructions and numbers.
* DNA is a template for amino acids and RNA, not a set of instructions (code) or table of facts (data).
* What DNA “describes” is probabilistic, dynamic, highly context-sensitive. It moves. Its parts move. Its environment moves. It’s chemistry. Object code is discrete and static. It’s math.
* DNA is hard to sequence. Object code is trivial to sequence.

Genomics today is like alchemy: we’re tinkering with a system we don’t understand in hopes of some elixir of longevity —except we call it “the cure for cancer.”

Why? Because we are impatient. Because we vastly over-estimate our ability to understand complex systems without simple abstractions. Because we believe what is difficult must be valuable. Because genomic research today is commercial, and gold must be made.

Well, that’s crap.

In software, we abstract object code with higher-level languages. When that system becomes too complex, we make a new, even higher level interface and abstract again. We continue until surface complexity is low enough to be useful.

In genomics, we label genes with some incomprehensible, ontologically-inconsistent name and then strain to make that gene “mean” some attribute or disease.

There is some use for the black-box, top-down genomic testing, but I believe that this approach alone is wrong. I believe that what we should be doing is creating better abstractions, interfaces, by which DNA can be understood. I believe that the future of genomics —the people who will make DNA mean something— will be the language designers who compile to DNA.

Until then, God laughs. There’s a reason why Window’s object code is everywhere, but the source code is top secret. Bill Gates laughs, too.

Tags: background, cancer, implementation, language, life, RNA, usefulness

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President Bush recently urged Congress to pass legislation to safeguard genetic privacy, a measure experts say would encourage millions of Americans to undergo genetic testing that could prevent disease.

“If a person is willing to share his or her genetic information, it is important that that information not be exploited in improper ways,” Mr. Bush said at the National Institutes of Health. For years, scientists and patients’ advocates have unsuccessfully pushed for legislation barring employers and insurance companies from discriminating based on the results of genetic tests. For the complete article, click here.

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WASHINGTON — Researchers at U.S. companies, nonprofit groups and government agencies are scouring the human genome for links to common diseases, promising a day when doctors will use a patient’s genetic profile to take preventative action.

One group of Americans accustomed to big sacrifices — military veterans
– soon will be asked to volunteer their DNA for that cause.
The Department of Veterans Affairs plans a genetic database from
potentially millions of VA patients, launching into profound legal,
ethical and privacy debates to claim a leading role in genetic medicine.
The VA intends to collect the first 100,000 samples in fiscal 2007,
which begins in October, and foresees a database as large as veterans
will allow. Read the full article here.

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A gene mutation found in some children may significantly influence how much they eat, according to a study presented Sunday at an annual meeting of the Obesity Society. Read more here.

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