Gene Characteristics

1. Gene Characteristics Relations between genes

2. Relationships between Genes • I. Between Alleles • Dominance – recessiveness • Co-dominance • Lethal and semi-lethal genes • Poly-allelism • Gene families • II. Between Non-alleles • Epistasis • Genetic heterogeneity

3. Ask your questions in due time!

4. Dominance – recessiveness • Genes that influence the PHENOTYPE both in the homozygous and the heterozygous state are dominant. Year introduced: 1968 • Genes that influence the PHENOTYPE only in the homozygous state are recessive. • ( 1968)

5. Dominance – recessiveness • A dominant trait refers to a genetic feature that hides the recessive trait in the phenotype of an individual. • A dominant trait is a phenotype that is seen in both the homozygous AA and heterozygous Aa genotypes. • For example Huntington Disease is an abnormal dominant trait in humans. • A dominant trait when written in a genotype is always written before the recessive gene in a heterozygous pair. A heterozygous genotype is written Aa, not aA

6. Dominance – recessiveness • Many traits are determined by pairs of complementary genes, each inherited from a single parent. • Often when these are paired and compared, one allele (the dominant) will be found to effectively shut out the instructions from the other, recessive allele. • For example, if a person has one allele IA and one i, that person will always have blood type A. • For a person to have blood type 0, both alleles must be i (recessive).

7. Dominance – recessiveness • When an individual has two dominant alleles, the condition is referred to as homozygous dominant (e.g. IA IA); • An individual with two recessive alleles is called homozygous recessive (e.g. ii). • An individual carrying one dominant and one recessive allele is referred to as heterozygous (e.g. Iai).

8. Words don’t come easy? • Repeat, exercise

10. Dominant Inheritance • If one of two parents (4. in the previous table) is affected by a genetic condition with a dominant inheritance pattern, every child has a one-in-two risk of being affected. • So on average half their children will be affected and half their children will not be affected and so will not pass on the condition. • However, as chance/probability determines inheritance, it is also possible that all or none of their children will be affected. • Examples of genetic conditions that show a dominant pattern of inheritance are Huntington’s disease, achondroplasia and neurofibromatosis.

11. Achondroplasia • People with this condition have an average body size, but shorter limbs. • This is because the bones in their arms and legs grow more slowly, both in the womb and throughout childhood. • Achondroplasia is one of the most common causes of short stature. • Most people with achondroplasia do not consider themselves disabled, just different. • Young children with achondroplasia may have hearing, speech or breathing problems but all of these can be treated.

12. Father and son, both with achondroplasia.

13. How is achondroplasia inherited? • People with achondroplasia may pass on the condition to their children. • If one parent is affected, each child has a one-in-two risk of having achondroplasia, and a one-in-two probability of being of average height (normal).

14. How is achondroplasia inherited? • If both parents have achondroplasia (An), children have a one in four chance of inheriting the gene from both parents, being thus homozygotes (AA) for the mutant gene. • Newborns who inherit both genes are considered to have a severe form of achondroplasia, where survival is usually less than 12 months after birth.

15. How is achondroplasia inherited? • If both parents have achondroplasia (An), children have a one in four chance of inheriting the gene from both parents, being thus homozygotes (AA) for the mutant gene. • Newborns who inherit both genes are considered to have a severe form of achondroplasia, where survival is usually less than 12 months after birth.

16. Average adult height of 131cm (4 feet, 3.8 inches) for males and 123 cm (4 feet, 0.6 inches) for females

17. The FGFR3 gene is responsible for causing achondroplasia. • FGFR3 is the acronym for fibroblast growth factor receptor 3 • Cytogenetic location of FGFR3 Gene : 4p16.3 • Molecular location on chromosome 4: from base pair 1,762,853 to base pair 1,777,828 • The protein plays a role in the development and maintenance of bone and brain tissue. • Researchers believe that this receptor regulates bone growth by limiting the formation of bone from cartilage, particularly in the long bones.

18. FGFR3 Function • This protein is part of the family of fibroblast growth factor receptors. These proteins are very similar and play a role in several important cellular functions, which include: • Regulation of cell growth and division • Determination of cell type • Formation of blood vessels • Wound healing • Embryo development.

19. Achondroplasia • Is a bonegrowth disorder • Cartilage has difficulty converting to bone, which results in dwarfism. • Although the word literally means "without cartilage formation,"the problem is not the formation of cartilage. The problem occurs when the cartilage has difficulty converting to bone, especially in the long bones of the arms and legs. • http://bones.emedtv.com/achondroplasia/achondroplasia.html

20. From cartilage to bone

21. Achondroplasia and FGFR3 Gene Function • The protein made by the FGFR3 gene is a receptor that regulates bone growth bylimiting the formation of bone from cartilage (a process called ossification), particularly in the long bones. • Researchers believe that mutations in the FGFR3 gene cause the receptor to be overly active, which interferes with ossification and leads to the disturbances in bone growth seen with this disorder. • This theory is supported by the knockout mouse model in which the receptor is absent, and so the negative regulation of bone formation is lost. The result is a mouse with excessively long bones and elongated vertebrae, resulting in a long tail.

22. Achondroplasia • Achondroplasia can be either inherited, or the result of a new mutation in the FGFR3 gene ; • In most cases (80 percent), the condition is due to a random, new, sporadic mutation of FGFR3. • Scientists know this because people with this type of achondroplasia have parents of average size (normal), but scientists do not know (yet) why this mutation occurs.

23. Achondroplasia • Achondroplasia can be detected before birth by the use of prenatalultrasound. • The diagnosis can be made by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended. • Additionally a DNA test can be performed before birth to detect homozygosity, where two copies of the mutant gene are inherited, a condition which is lethal and leads to stillbirths.

24. The left image is a radiograph of the hand of a young patient with achondroplasia. The characteristic "trident" deformity is present, consisting of separation of the first and second as well as the third and fourth digits. Notice the shortened tubular bones of the hand, particularly the proximal phalanges. The right image is of an adult. To identify are the short tubular bones with a gracile distal ulna, characteristic of achondroplasia.

25. Achondroplasia • No cure for achondroplasia currently exists. Therefore, achondroplasia treatment involves preventing or treating the signs, symptoms, or health conditions that occur as a result of the disorder. • Health problems commonly associated with achondroplasia that may require treatment include: • Reduced muscle strength • Recurring ear infections • Breathing disorders (apnea) • Obesity • Crowded teeth. • Social and family support, along with regular follow-up visits with healthcare providers, are also an important part of achondroplasia treatment.

26. Achondroplasia • Characteristic symptoms include: • An average-size trunk. • Short arms and legs, with particularly short upper arms and thighs. • An enlarged head with a prominent forehead. • Fingers that are typically short. The ring finger and middle finger may diverge, giving the hand a trident appearance.

27. Achondroplasia is one of the most common causes of dwarfism. Characteristics of a person with the disease include: A short stature with proportionately short arms and legs A large head (macrocephaly), A prominent forehead (frontal bossing) A flattened bridge of the nose.

28. Dominance – recessiveness • An example of an autosomal dominant human disorder is Huntington's disease (HD), which is a neurological disorder resulting in impaired motor function. • The mutant allele results in an abnormal protein, containing large repeats of the amino acidglutamine. This defective protein is toxic to neural tissue, resulting in the characteristic symptoms of the disease. • Hence, one copy of the deffective gene is sufficient to confer the disorder to the person carrying it.

29. 1983Scientists discover a gene marker linked to HD on the short arm of chromosome 4, which indicates that the Huntington gene is also located on chromosome 4. Predictive linkage testing is introduced to assess the likelihood of contracting HD.

30. Huntington disease (HD) • Huntington disease (HD) is a disorder affecting nerve cells in the brain.

31. 1993The location of the Huntington gene is discovered at the 4p16.3 gene site on chromosome 4. The gene is found to contain codon C-A-G in varying numbers. An abnormal number of CAG repeats turns out to be a highly reliable way to tell whether someone has the allele for HD.

32. Do not loose your enthusiasm, there is still more to find out

33. Huntington disease (HD) • Huntington's disease is one of several trinucleotide repeat disorders, caused by the length of a repeated section of a gene exceeding the normal range. The huntingtingene (HTT) normally provides the information to produce Huntingtin protein, but when affected, produces mutant Huntingtin (mHTT) instead.

34. Huntington disease (HD) • It is an inherited progressive neurodegenerative disorder characterized by: • choreiform movements (uncoordinated, jerky body movements), • psychiatric problems, and • dementia (decline in some mental abilities)

35. Huntington disease (HD) • This geneticneurological disorder itself isn't fatal, but as symptoms progress, complications reducing life expectancy increase. • Abnormal movements are initially exhibited as general lack of coordination, an unsteady gait and slurring of speech, but, as the disease progresses, any function that requires muscle control is affected, causing physical instability, abnormal facial expression, but the most characteristic physical symptoms are jerky, random, and uncontrollable movements called chorea.

36. Huntington disease • Mild symptoms, which include forgetfulness, clumsiness and personality changes first appear in middle age. • Over the next 10-20 years, a person with HD gradually loses all control of their mental and physical abilities. • There is no cure for HD at the moment, although some of the symptoms can be treated with drugs.

37. Huntington disease (Huntington chorea) • The advances in molecular genetics make it possible to detect Huntington disease in a preclinical stage at or even before birth. • The molecular approach does not replace prior approaches to Huntington disease but is synergistic and provides a model of the new genetics.

38. Huntington disease (HD) • The Huntingtingene (HTT), also called HD (Huntington disease) gene, or the IT15 ("interesting transcript 15") gene is located on the short arm of chromosome 4 (4p16.3). • HTT contains a sequence of three DNAbases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ...CAGCAGCAG...) on its 5' end, known as a trinucleotide repeat/codon. • CAG is coding for the amino acidglutamine, so a series of them results in the production of a chain of glutamine known as polyglutamine or polyQ tract, and the repeated part of the gene, the PolyQ region

39. Where is the HTT gene located? Cytogenetic Location: 4p16.3 Molecular Location on chromosome 4: base pairs 3,046,205 to 3,215,484

40. Huntington disease (HD) • Huntington disease is caused by a abnormal trinucleotide (CAG) expansion in the HD gene • Normal persons have a CAG repeat count of between 7 and 35 repeats • HTT gene encodes the protein huntingtin, and if abnormal resulting in an expanded polyglutamine tract. • Huntingtin is present in a large number of tissues throughout the body, with the highest levels of expression seen in the brain.

41. Huntingtin • The exact function of this protein is yet not known, but it plays an important role in nerve cells. • Within cells, huntingtin may be involved in • signaling, • transporting materials, • binding proteins and other structures, and • protecting against programmed cell death (apoptosis). • Huntingtin protein is required for normal development beforebirth.

42. Huntingtondisease (HD) • The pathophysiology of HD is not fully understood, although it is thought to be related to toxicity of the mutant huntingtin protein. • However, pathology appears to be limited to the central nervous system, with atrophy of the caudate and putamen (the neostriatum) being most prominent. • At the cellular level, protein aggregates are seen both in the cytoplasm and nucleus.

43. Huntington disease (HD) • Although most cases start clinically in midadulthood, usually between 35 and 42 years of age, there is great variability in age of onset. • About 3% of cases are diagnosed as juvenile Huntington disease before the age of 15 years. Late onset is well known after 50 years of age.

44. Huntington disease (HD) • Generally, the number of CAG repeats is related to how much the person is affected, and correlates with age at onset and the rate of progression of symptoms. • For example, 36–39 repeats result in much later onset and slower progression of symptoms than the mean of ill persons, such that some individuals may die of other causes before they even manifest symptoms of Huntington disease, this is termed "reduced/incompletepenetrance”

45. There is a variation in age of onset for any given CAG repeat length, particularly within the intermediate range (40–50 CAGs). For example, a repeat length of 40 CAGs leads to an onset ranging from 40 to 70 years of age in one study. This variation means that, althoughalgorithmshave been proposed for predicting the age of onset, in practice, it can not be predicted confidently

46. Understanding HD • The symptoms of Huntington disease (HD) appear when an abnormal protein builds up in nerve cells in certain areas of the brain, causing the cells to die. • One of the brain areas affected is the area that controls movement. • Cells in the outer layer of the brain also die, affecting mental abilities. • Brain scan from a patient with Huntington disease (right) showing a larger cavity where brain cells have died, compared with a normal brain (left). (arrows)

47. Testing for HD As the symptoms of Huntington disease (HD) do not usually appear until middle age, some people only discover they are at risk when one of their parents or grandparents is diagnosed. A genetic test is available to HD families that can tell people whether or not they have inherited the altered gene,but not the age at which they will start to develop symptoms. Although there is no cure available at the moment, genetic tests can help people at risk of HD make decisions about their future. However most decide not to take the test. DNA analysis of Huntington’s disease. Each lane shows a different person's DNA: two bands in the normal (N) range show someone is unaffected. One band in the H range predicts the person will get Huntington disease.

48. How is HD inherited? • Huntington disease (HD) is caused by a single altered gene, which is passed on from one generation to the next in affected families • With one affected parent, each child has a one-in-two chance of inheriting HD. • Children who do not carry the altered gene are free from the condition and cannot not pass it on to their own children

49. Testing for HD • Genetic testing may infer information about relatives who do not want it. • Testing a descendant of an undiagnosed parent has implications to other family members, since a positive result automatically reveals the parent as carrying the affected gene, and siblings (and especially identical twins) as being 'at risk' of also inheriting it. • This emphasizes the importance of disclosure, as individuals have to decide when and how to reveal the information to their children and other family members. • For those at risk, or known to carry a mutant allele, there can be the consideration of prenatal genetic testing in order to ensure that the disorder is not passed on.

50. Testing for HD • Embryonic screening is another possibility for affected or at-risk individuals to know if their children will or will not inherit the disease. • It is possible for women who would consider abortion of an affected fetus to test an embryo in the womb (prenatal diagnosis). • Other techniques, such as preimplantation genetic diagnosis in the setting of in vitro fertilisation, can be used to ensure that the newborn is unaffected