Hardy-Weinberg principle

The Hardy-Weinberg principle states that when no evolution occurs in a population, the allele and genotype frequencies do not change from one generation to the next. No evolution refers to no mutation, no gene flow, no natural selection, and no genetic drift. To be in equilibrium two more assumptions need to be made that random mating occurs and there are discrete, non-overlapping generations.

Mitochondrial dna

In addition to nuclear DNA, humans (like almost all eukaryotes) have mitochondrial DNA. Mitochondria, the "power houses" of a cell, have their own DNA because they are descended from a proteobacterium that merged with eukaryotic cells over 2 billion years ago—an assertion known as the endosymbiotic hypothesis. Mitochondria are inherited from one's mother, and its DNA is frequently used to trace maternal lines of descent (see mitochondrial Eve). Mitochondrial DNA is only 16kb in length and encodes for 62 genes.

Genes and gender

Main article: XY sex-determination system

X-linked traits

Main article: Sex linkage

Sex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance. Since humans have many more genes on the X than the Y, there are many more X-linked traits than Y-linked traits. However, females carring two or more copies of the X chromosome, resulting in a potentially toxic dose of X-linked genes. To correct this imbalance, mammalian females have evolved a unique mechanism of dosage compensation. In particular, by way of the process called X-chromosome inactivation (XCI), female mammals transcriptionally silence one of their two Xs in a complex and highly coordinated manner.^[4]

X-link Dominant	X-link Recessive	References
Alport syndrome	absence of blood in urine
Coffin-Lowry syndrome	no cranial malformations
colour vision	colour blindness
normal clotting factor	haemophilia A & B
Strong muscle tissue	Duchenne Muscular Dystrophy
fragile X syndrome	normal X chromosome
Aicardi syndrome	absence of brain defects
absence of autoimmunity	IPEX syndrome
Xg Blood type	absence of antigen
production of GAGs	Hunter syndrome
normal muscle strength	Becker's muscular dystrophy
unaffected body	Fabry's disease
no progressive blindness	Choroideremia
no kidney damage	Dent's disease
Rett syndrome	no microcephaly
production of HGPRT	Lesch–Nyhan syndrome
high levels of copper	Menkes disease
normal immune levels	Wiskott–Aldrich syndrome
Focal dermal hypoplasia	normal pigmented skin
normal pigment in eyes	Ocular albinism
vitamin D resistant rickets	absorption of vitamin D
Synesthesia	non colour perception

Bibliography

Freud, Sigmund, (1905d) Three Essays on the Theory of Sexuality. SE, 7: 123-243.

——. (1916-1917a). Introductory lectures on psychoanalysis. SE, 16.

Kaës, René (1993). Introduction. In René Kaës, et al., Transmission de la vie psychique entre générations. Paris: Dunod.

Sulloway, Frank J. (1979). Freud—biologist of the mind. London: Burnett.

Topic №12

Genetic disease prevention and gene therapy

Prepared by Kassymova Symbat

WHAT IS GENE THERAPY?

Imagine that you accidentally broke one of your neighbor's windows. What would you do? You could: Stay silent: no one will ever find out that you are guilty, but the window doesn't get fixed. Try to repair the cracked window with some tape: not the best long-term solution. Put in a new window: not only do you solve the problem, but also you do the honorable thing. What does this have to do with gene therapy? You can think of a medical condition or illness as a "broken window." Many medical conditions result from flaws, or mutations, in one or more of a person's genes. Mutations cause the protein encoded by that gene to malfunction. When a protein malfunctions, cells that rely on that protein's function can't behave normally, causing problems for whole tissues or organs. Medical conditions related to gene mutations are called genetic disorders. So, if a flawed gene caused our "broken window," can you "fix" it? What are your options? Stay silent: ignore the genetic disorder and nothing gets fixed. Try to treat the disorder with drugs or other approaches: depending on the disorder, treatment may or may not be a good long-term solution. Put in a normal, functioning copy of the gene: if you can do this, it may solve the problem! If it is successful, gene therapy provides a way to fix a problem at its source. Adding a corrected copy of the gene may help the affected cells, tissues and organs work properly. Gene therapy differs from traditional drug-based approaches, which may treat the problem, but which do not repair the underlying genetic flaw. But gene therapy is not a simple solution - it's not a molecular bandage that will automatically fix a disorder. Although scientists and physicians have made progress in gene therapy research, they have much more work to do before they can realize its full potential. In this module, you'll explore several approaches to gene therapy, try them out yourself, and figure out why creating successful gene-based therapies is so challenging.

CHOOSING TARGETS FOR GENE THERAPY

Gene therapy could potentially treat certain disorders at the source by repairing the underlying genetic flaws. Many disorders or medical conditions might be treated using gene therapy, but others may not be suitable for this approach.

How do you know whether a disorder is a good candidate for gene therapy?

For any candidate disorder, you need to answer the following questions:

1. Does the condition result from mutations in one or more genes? For you to even consider gene therapy, the answer must be "yes."

2. Which genes are involved? If you plan to treat a genetic flaw, you need to know which gene(s) to pursue. You must also have a DNA copy of that gene available in your laboratory. The best candidates for gene therapy are the so-called "single-gene" disorders - which are caused by mutations in only one gene.

3. What do you know about the biology of the disorder? To design the best possible approach, you need to learn all you can about how the gene factors into the disorder. For example: 

   • Which tissues are affected?

   • What role does the protein encoded by the gene play within the cells of that tissue?

   • Exactly how do mutations in the gene affect the protein's function?

4. Will adding a normal copy of the gene fix the problem in the affected tissue? This may seem like an obvious question, but it's not. What if the mutated gene encodes a protein that prevents the normal protein from doing its job? Mutated genes that function this way are called dominant negative and adding back the normal protein won't fix the problem. Learn more about how researchers are trying to address dominant negative mutated genes in New Approaches to Gene Therapy.

5. Can you deliver the gene to cells of the affected tissue? The answer will come from several pieces of information, including:

   • How accessible is the tissue? Is it fairly easy (skin, blood or lungs), or more difficult to reach (internal organs)?

   • What is your best mode of delivery? You can examine the pros and cons of potential delivery methods in Tools of the Trade.

If you can answer "yes" to Questions 4 and 5, then the disorder may be a good candidate for a gene therapy approach.

What is genetic screening?

Realization of these great projects and others like them, requires the collecting, sequencing and comparison of many DNA genomes from different individuals and populations. In other words, it requires a massive and exhaustive genetic screening of individuals and populations.

Some institution such as the U.S. Congress Office of Technology Assessment (OTA) differentiates genetic testing from genetic screening. The first is defined as "the use of specific assays to determine the genetic status of individual already suspected to be at risk for a particular inherited condition," whereas genetic screening is using the same probe or assay, but distinguished from genetic testing by analyzing a target population. However, the most of the reports are using testing and screening interchangeably. The National Academy of Sciences (NAS) defines genetic screening as the systematic search of population for persons with latent, early, or asymptomatic disease (12). Also, in agreement with the HDP, genetic screening searches for disabling genes that, for instance, may confer resistance to specific diseases (10). Another purpose of genetic screening is to determine polymorphism that can be used as a simple genetic characterization of a population.

For medical studies, genetic screening is normally done to check for certain genes that potentially produce damaging changes in the individuals. So early detection may help to avoid its consequence. In this sense, genetic probes are useful for both prenatal diagnosis and newborn screening for detect rare metabolic diseases such as phenylketonuria (PKU), a disease which causes mental retardation and can be prevented by following a special diet, sickle cell anemia and Ashkenazic Jews for Tay-Sach disease. Screening is also useful to identify individuals that are carriers of a chromosome abnormality or gene that may cause problems for either the offspring or the person screened. During the last years probes for cystic fibrosis, Duchenne muscular dystrophy, hemophilia, Huntington'disease, neurofibromatosis and brain cancer have been developed (6, 9).

Associations between a gene and a disease can often be established by linkage studies. Using polymorphic markers which can be found in the population with a relatively high frequency, relatives (e.g., siblings) affected by a disease are identified. Then, if during this study, one form of one marker (or of a close linked marker) is found significantly more often than expected by chance, this marker is said to be close (or "linked") to the disease-related gene. However, some aberrant genes, such as the one for phenylketonuria (PKU) was inferred from the discovery that metabolites of phenylalanine, an amino acid, was increased in people with PKU. Following this discovery, the activity of the enzyme that catalyzed the conversion of phenylalanine to tyrosine was found to be absent or decreased in patients with PKU. Recently, with the advent of recombinant DNA technology the gene catalyzing this conversion was localized to chromosome 12 (9).

The application and scope of genetic markers is limited to studying the intrinsic features of genetic diseases, such as heterogeneity and incomplete penetrance, which reduce, respectively, the clinical sensitivity and positive predictive value of a genetic test (9).

Social dilemmas of genetic screening

The use of a genetic marker to predict early genetic disorders can be beneficial to the society, so we may prevent symptom development with early medical assistance. But, for instance, in many cases, if a genetic disease is detected in a fetus, the fetus is aborted. Also, there are cases of people that carry DNA mutations associated with a genetic disease, that are being discriminated by health insurers and employer (8). So, the genetic screening is bringing new social, legal and ethical dilemmas.

ELSI (Ethical Legal and Social Issue) working group (5), which is a special committee of HUGO (Human Genome Organization) discusses the social consequences of HGP. At its first meeting, in 1989, they identified topics that required special attention. These were fair use of genetic test information in areas such as insurance, employment, criminal justice, education, adoption and in military aspects; impact of genetic information on individuals; personal privacy and confidentiality of genetic information; the impact that the dramatic increase in human genetic information will have on genetic counseling and the delivery of genetic services; influence of genetic information and new technologies on reproductive decisions; issues raised by the introduction of new genetic information and technologies into mainstream medical practice; historical analysis of the use and misuse of genetic information and technologies; issues raised regarding the commercialization of researching results and conceptual and philosophical topics, related to human genetics.

Many leading countries in genetic research, such as USA, England, Japan, France, have extensively debate the ethical, legal and social aspects of genetic screening. Consequently, each country has its own committee that is working to identify and define issues and develop policy options to address them according to its own social-political situation.

Unites States citizens want to avoid genetic discrimination by health insurers and employers

In the United States, the most important public debate is related to possible genetic discrimination and health insurance . It is based on the fact that in the past, genetic information has been used by insurers to discriminate against people. In the early 1970s, some insurance companies denied coverage and charged higher rates to African Americans who carried the gene for sickle anemia. Nowadays, some cases of genetic discrimination against people who are healthy but have a gene that predisposes them or their children to diseases later in life such as Huntington's disease, have been reported. In a recent survey, 22% of the people with a known genetic condition in the family, indicated that health insurance coverage has been denied to them due to their genetic status (8).

Hudson et al, in "Genetic Discrimination and Health Insurance: an Urgent Need for Reform" (8) recommended and defined some actions and concepts to federal policy markers, to protect society from genetic discrimination. This recommendation is that insurance providers should be either prohibited from using genetic information, or an individual's request for genetic services, to deny or limit any coverage or establish eligibility, continuation, enrollment, or contribution requirements. Moreover, providers should be prohibited from establishing differential rates or premium payments based on genetic information or an individual' request for genetic services and, they should be prohibited from requesting or requiring collection or disclosure of genetic information. Also, insurance providers and the holders of genetic information should be prohibited from releasing genetic information without prior written authorization of the individual. They defined genetic information as information about genes, genes' products, or inherited characteristics they may derive from the individual or family member and insurance providers were defined as an insurance company, employer, or any other entity providing a plan of health insurance or health benefits including group and individual health plans either fully insured or self-funded.

Those who agree that genetic screening positively affects the medical care of individual patients and see a need to ensure the freedom of patients, last year presented a bill to the Committee on Labor and Human Resources (15). This bills is titled "The genetic confidentiality and nondiscrimination act of 1996". It proposes the definition of the circumstances under which genetic information may be created, stored, analyzed, or disclosed, and defines the rights of individual and persons in relation to genetic information; responsibilities of others in respect to genetic information; protection of individuals from genetic discrimination; establishment of uniform rules that protects individual genetic privacy and allows the advancement of genetic research and establishment of effective mechanisms to enforce the rights and responsibilities.

Health insurance providers state, said that the impact of genetic information on insurance rates and availability is in some cases exaggerated. And that restrictions as the ones mentioned above, which forbid health insurance companies from using information to deny coverage to potential clients, are not appropriate for the viability and profitability of insurance companies. Moreover, genetic information is often costly to obtain, and the benefits of reducing claim cost may not be commensurate with the cost of obtaining the information on the numerous applicants screened every day by insurance companies (2, 3).

Some people think that genetic screening may be used to identify good genome (3), so, those with it will insist on better rates by the insurers. Unlike negative discrimination, an eventual positive discrimination could have a positive effect on genetic research and preventive medicine by encouraging people to participate in genetic tests. But it would raise exactly the same social and ethical issues because insurers, under competitive pressure, would have to lower rates for individuals with a low genetic risk and consequently increase rates for those with a high genetic risk. So, insurers responding to new market demand, will design new products with limited coverage and lower rates, which will be the preferred choice of customers who know they have a genetically low risk, whereas people who know they have a higher risk will incline towards more extensive coverage with higher rates.

In the last months, the US Senate approved, unanimously, a health reform bill that explicitly bars insurers from using genetic information to deny coverage to applicants. The main goal of the Senate bill, whose authors were Senators Nancy Kassebaum and Edward Kennedy, is to prevent people from losing health insurance when they change or leave jobs (7).