Wednesday, December 9, 2009

Interactions of multiple genes

Organisms have thousands of genes, and in sexually reproducing organisms assortment of these genes are generally independent of each other. This means that the inheritance of an allele for yellow or green pea color is unrelated to the inheritance of alleles for white or purple flowers. This phenomenon, known as "Mendel's second law" or the "Law of independent assortment", means that the alleles of different genes get shuffled between parents to form offspring with many different combinations.(Some genes do not assort independently, demonstrating genetic linkage, a topic discussed later in this article.)

Often different genes can interact in a way that influences the same trait. In the Blue-eyed Mary (Omphalodes verna), for example, there exists a gene with alleles that determine the color of flowers: blue or magenta. Another gene, however, controls whether the flowers have color at all: color or white. When a plant has two copies of this white allele, its flowers are white - regardless of whether the first gene has blue or magenta alleles. This interaction between genes is called epistasis, with the second gene epistatic to the first.[30]

Many traits are not discrete features (eg. purple or white flowers) but are instead continuous features (eg. human height and skin color). These complex traits are the product of many genes.[31] The influence of these genes is mediated, to varying degrees, by the environment an organism has experienced. The degree to which an organism's genes contribute to a complex trait is called heritability.[32] Measurement of the heritability of a trait is relative - in a more variable environment, the environment has a bigger influence on the total variation of the trait. For example, human height is a complex trait with a heritability of 89% in the United States. In Nigeria, however, where people experience a more variable access to good nutrition and health care, height has a heritability of only 62%.

Discrete inheritance and Mendel's laws

At its most fundamental level, inheritance in organisms occurs by means of discrete traits, called genes.[24] This property was first observed by Gregor Mendel, who studied the segregation of heritable traits in pea plants.[9][25] In his experiments studying the trait for flower color, Mendel observed that the flowers of each pea plant were either purple or white – and never an intermediate between the two colors. These different, discrete versions of the same gene are called alleles.

In the case of pea, which is a diploid species, each individual plant has two alleles of each gene, one allele inherited from each parent.[26] Many species, including humans, have this pattern of inheritance. Diploid organisms with two copies of the same allele of a given gene are called homozygous at that gene locus, while organisms with two different alleles of a given gene are called heterozygous.

The set of alleles for a given organism is called its genotype, while the observable traits of the organism are called its phenotype. When organisms are heterozygous at a gene, often one allele is called dominant as its qualities dominate the phenotype of the organism, while the other allele is called recessive as its qualities recede and are not observed. Some alleles do not have complete dominance and instead have incomplete dominance by expressing an intermediate phenotype, or codominance by expressing both alleles at once.[27]

When a pair of organisms reproduce sexually, their offspring randomly inherit one of the two alleles from each parent. These observations of discrete inheritance and the segregation of alleles are collectively known as Mendel's first law or the Law of Segregation.

History of Genetics

Although the science of genetics began with the applied and theoretical work of Gregor Mendel in the mid-1800s, other theories of inheritance preceded Mendel. A popular theory during Mendel's time was the concept of blending inheritance: the idea that individuals inherit a smooth blend of traits from their parents. Mendel's work disproved this, showing that traits are composed of combinations of distinct genes rather than a continuous blend. Another theory that had some support at that time was the inheritance of acquired characteristics: the belief that individuals inherit traits strengthened by their parents. This theory (commonly associated with Jean-Baptiste Lamarck) is now known to be wrong—the experiences of individuals do not affect the genes they pass to their children.[7] Other theories included the pangenesis of Charles Darwin (which had both acquired and inherited aspects) and Francis Galton's reformulation of pangenesis as both particulate and inherited.[8]

Mendelian and classical genetics

The modern science of genetics traces its roots to Gregor Johann Mendel, a German-Czech Augustinian monk and scientist who studied the nature of inheritance in plants. In his paper "Versuche über Pflanzenhybriden" ("Experiments on Plant Hybridization"), presented in 1865 to the Naturforschender Verein (Society for Research in Nature) in Brünn, Mendel traced the inheritance patterns of certain traits in pea plants and described them mathematically.[9] Although this pattern of inheritance could only be observed for a few traits, Mendel's work suggested that heredity was particulate, not acquired, and that the inheritance patterns of many traits could be explained through simple rules and ratios.

The importance of Mendel's work did not gain wide understanding until the 1890s, after his death, when other scientists working on similar problems re-discovered his research. William Bateson, a proponent of Mendel's work, coined the word genetics in 1905.[10][11] (The adjective genetic, derived from the Greek word genesis - γένεσις, "origin" and that from the word genno - γεννώ, "to give birth", predates the noun and was first used in a biological sense in 1860.)[12] Bateson popularized the usage of the word genetics to describe the study of inheritance in his inaugural address to the Third International Conference on Plant Hybridization in London, England, in 1906.[13]

After the rediscovery of Mendel's work, scientists tried to determine which molecules in the cell were responsible for inheritance. In 1910, Thomas Hunt Morgan argued that genes are on chromosomes, based on observations of a sex-linked white eye mutation in fruit flies.[14] In 1913, his student Alfred Sturtevant used the phenomenon of genetic linkage to show that genes are arranged linearly on the chromosome.[15]

Molecular genetics

Although genes were known to exist on chromosomes, chromosomes are composed of both protein and DNA—scientists did not know which of these is responsible for inheritance. In 1928, Frederick Griffith discovered the phenomenon of transformation (see Griffith's experiment): dead bacteria could transfer genetic material to "transform" other still-living bacteria. Sixteen years later, in 1944, Oswald Theodore Avery, Colin McLeod and Maclyn McCarty identified the molecule responsible for transformation as DNA.[16] The Hershey-Chase experiment in 1952 also showed that DNA (rather than protein) is the genetic material of the viruses that infect bacteria, providing further evidence that DNA is the molecule responsible for inheritance.[17]

James D. Watson and Francis Crick determined the structure of DNA in 1953, using the X-ray crystallography work of Rosalind Franklin and Maurice Wilkins that indicated DNA had a helical structure (i.e., shaped like a corkscrew).[18][19] Their double-helix model had two strands of DNA with the nucleotides pointing inward, each matching a complementary nucleotide on the other strand to form what looks like rungs on a twisted ladder.[20] This structure showed that genetic information exists in the sequence of nucleotides on each strand of DNA. The structure also suggested a simple method for duplication: if the strands are separated, new partner strands can be reconstructed for each based on the sequence of the old strand.

Although the structure of DNA showed how inheritance works, it was still not known how DNA influences the behavior of cells. In the following years, scientists tried to understand how DNA controls the process of protein production. It was discovered that the cell uses DNA as a template to create matching messenger RNA (a molecule with nucleotides, very similar to DNA). The nucleotide sequence of a messenger RNA is used to create an amino acid sequence in protein; this translation between nucleotide and amino acid sequences is known as the genetic code.

With this molecular understanding of inheritance, an explosion of research became possible. One important development was chain-termination DNA sequencing in 1977 by Frederick Sanger: This technology allows scientists to read the nucleotide sequence of a DNA molecule.[21] In 1983, Kary Banks Mullis developed the polymerase chain reaction, providing a quick way to isolate and amplify a specific section of a DNA from a mixture.[22] Through the pooled efforts of the Human Genome Project and the parallel private effort by Celera Genomics, these and other techniques culminated in the sequencing of the human genome in 2003.[23]

Klinefelter's Syndrome

Klinefelter's syndrome, 47, XXY or XXY syndrome is a condition in which males have an extra X sex chromosome. While females have an XX chromosomal makeup, and males an XY, affected individuals have at least two X chromosomes and at least one Y chromosome.[1] Klinefelter's syndrome is the most common sex chromosome disorder[2] and the second most common condition caused by the presence of extra chromosomes. The condition exists in roughly 1 out of every 1,000 males. One in every 500 males have an extra X chromosome but do not have the syndrome.[3]

The principal effects are development of small testicles and reduced fertility. A variety of other physical and behavioral differences and problems are common, though severity varies and many boys and men with the condition have few detectable symptoms. The syndrome was named after Dr. Harry Klinefelter, an endocrinologist at Massachusetts General Hospital in Boston, Massachusetts, who first described it in 1942.[4] Because of the extra chromosome, individuals with the condition are usually referred to as "XXY Males", or "47, XXY Males".[5]Signs and symptoms

Affected males are almost always effectively infertile, although advanced reproductive assistance is sometimes possible.[6] Some degree of language learning impairment may be present,[7] and neuropsychological testing often reveals deficits in executive functions.[8] In adults, possible characteristics vary widely and include little to no signs of affectedness, a lanky, youthful build and facial appearance, or a rounded body type with some degree of gynecomastia (increased breast tissue).[9] Gynecomastia is present to some extent in about a third of affected individuals, a slightly higher percentage than in the XY population, but only about 10% of XXY males' gynecomastia is noticeable enough to require surgery.[10]

The term hypogonadism in XXY symptoms is often misinterpreted to mean "small testicles" or "small penis". In fact, it means decreased testicular hormone/endocrine function. Because of this hypogonadism, patients will often have a low serum testosterone level but high serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) levels.[11] Despite this misunderstanding of the term, however, it is true that XXY men often also have microorchidism (i.e. small testicles).[11]

The more severe end of the spectrum of symptom expression is also associated with an increased risk of germ cell tumors, breast cancer,[12] and osteoporosis,[3] risks shared to varying degrees[13] with females. Additionally, medical literature shows some individual case studies of Klinefelter's syndrome coexisting with other disorders, such as pulmonary disease, varicose veins, diabetes mellitus, and rheumatoid arthritis, but possible correlations between Klinefelter's and these other conditions are not well characterized or understood.[citation needed]

In contrast to these potentially increased risks, it is currently thought that rare X-linked recessive conditions occur less frequently in XXY males than in normal XY males, since these conditions are transmitted by genes on the X chromosome, and people with two X chromosomes are typically only carriers rather than affected by these X-linked recessive conditions.

There are many variances within the XXY population, just as in the most common 46,XY population. While it is possible to characterise 47,XXY males with certain body types, that in itself should not be the method of identification as to whether or not someone has 47,XXY. The only reliable method of identification is karyotype testing.

Turner Syndrome

Turner syndrome or Ullrich-Turner syndrome (also known as "Gonadal dysgenesis"[1]:550) encompasses several conditions, of which monosomy X (absence of an entire sex chromosome) is most common. It is a chromosomal disorder in which all or part of one of the sex chromosomes is absent (unaffected humans have 46 chromosomes, of which 2 are sex chromosomes). Typical females have 2 X chromosomes, but in Turner syndrome, one of those sex chromosomes is missing or has other abnormalities. In some cases, the chromosome is missing in some cells but not others, a condition referred to as mosaicism[2] or 'Turner mosaicism'.

Occurring in 1 out of every 2500 girls, the syndrome manifests itself in a number of ways. There are characteristic physical abnormalities, such as short stature, swelling, broad chest, low hairline, low-set ears, and webbed necks.[3] Girls with Turner syndrome typically experience gonadal dysfunction (non-working ovaries), which results in amenorrhea (absence of menstrual cycle) and sterility. Concurrent health concerns are also frequently present, including congenital heart disease, hypothyroidism (reduced hormone secretion by the thyroid), diabetes, vision problems, hearing concerns, and many other autoimmune diseases.[4] Finally, a specific pattern of cognitive deficits is often observed, with particular difficulties in visuospatial, mathematical, and memory areas.[5]

Common symptoms of Turner syndrome include:

* Short stature
* Lymphedema (swelling) of the hands and feet
* Broad chest (shield chest) and widely-spaced nipples
* Low hairline
* Low-set ears
* Reproductive sterility
* Rudimentary ovaries gonadal streak (underdeveloped gonadal structures)
* Amenorrhea, or the absence of a menstrual period
* Increased weight, obesity
* Shield shaped thorax of heart
* Shortened metacarpal IV (of hand)
* Small fingernails
* Characteristic facial features
* Webbed neck from cystic hygroma in infancy
* Coarctation of the aorta
* Poor breast development
* Horseshoe kidney
* Visual impairments sclera, cornea, glaucoma, etc.
* Ear infections and hearing loss