Medical genetics Medical genetics is one of the most rapidly advancing fields of medicine, and molecular genetics is now integral to all aspects of biomedical science. Every physician who practices in the 21st century must have an in-depth knowledge of the principles of human genetics and their application to a wide variety of clinical problems.

What is a genetic disorder? A genetic disorder is a disease or defect that is inherited. Genetic disorders are not always noticeable at birth.

Genetic disorders are inherited in one of three ways: From one generation to the next When each parent is the carrier of a genetic disorder. (These parents do not have the disorder, but can pass the genes on to their children.) Because of a change in the genetic information being passed on.

What is a birth defect? A birth defect is an abnormality present at birth. Not all birth defects are inherited. Some birth defects may result from….

Classification of Genetic Diseases Single gene mendelian medical disorders Chromosomal disorders Multifactorial inheritance Mitochondria inheritance Somatic mutation

Euchromatin and Heterochromatin Chromosomes may be identified by regions that stain in a particular manner when treated with various chemicals. Several different chemical techniques are used to identify certain chromosomal regions by staining then so that they form chromosomal bands. For example, darker bands are generally found near the centromeres or on the ends (telomeres) of the chromosome, while other regions do not stain as strongly. The position of the dark-staining are heterochromatic region or heterochromatin. Light staining are euchromatic region or euchromatin.

Heterochromatin is classified into two groups: (i) Constitutive and (ii) Facultative. Constitutive heterochromatin remains permanently in the heterochromatic stage, i.e., it does not revert to the euchromatic stage. In contrast, facultative heterochromatin consists of euchromatin that takes on the staining and compactness characteristics of heterochromatin during some phase of development.

Autosomal X-Linked Y-Linked Mitoch ondrial Total 9443 418 48 37 9946   Autosomal X-Linked Y-Linked Mitoch ondrial Total * Gene with known sequence 9443 418 48 37 9946 + Gene with known sequence   and phenotype 353 38 391 # Phenotype description,   molecular basis known 1506 137 2 27 1672 % Mendelian phenotype or locus,   molecular basis unknown 1303 132 4 1439 Other, mainly phenotypes with suspected mendelian basis 2166 154 2322 14771 879 56 64 15770

OMIM Statistics for September 24, 2007 Number of Entries Autosomal X-Linked Y-Linked Mitocho ndrial Total Gene with known sequence 11222 522 48 37 11829 Gene with known sequence   and phenotype 352 30 382 Phenotype description,   molecular basis known 1957 184 2 26 2169 Mendelian phenotype or locus,   molecular basis unknown 1464 130 4 1598 Other, mainly phenotypes with suspected mendelian basis 1976 142 2120 16971 1008 56 63 18098

Total number of loci: 9171 Chr. Loci 1 870 2 568 3 491 4 348 5 435 6 Synopsis of the Human Gene Map Chr.    Loci 1  870  2  568  3  491  4  348  5  435  6  566  7  421  8  324  Chr.    Loci 9  326  10  308  11  578  12  476  13  158  14  277  15  263  16  347  Chr    Loc 17  531  18  137  19  601  20  215  21  119  22  228  X  538  Y  46 

OMIM Statistics for October 5, 2009   Autosomal X-Linked Y-Linked Mitochondrial Total * Gene with known sequence 12258 602 48 35 12943 + Gene with known sequence   and phenotype 332 22 2 356 # Phenotype description,   molecular basis known 2365 209 4 26 2604 % Mendelian phenotype or locus,   molecular basis unknown 1644 141 5 1790 Other, mainly phenotypes with suspected mendelian basis 1880 139 2021 18479 1113 59 63 19714

Synopsis of the Human Gene Map Chr.    Loci 1  1194  2  769  3  647  4  463  5  569  6  729  7  534  8  445  Chr.    Loci 9  457  10  446  11  761  12  641  13  222  14  376  15  356  16  467  Chr.    Loci 17  705  18  173  19  766  20  304  21  141  22  301  X  689  Y  45  Total number of loci: 12200

Total number of loci: 10432 Synopsis of the Human Gene Map Chr. Loci 1 1  1009  2  644  3  565  4  388  5  494  6  626  7  460  8  365  Chr.    Loci 9  387  10  363  11  648  12  549  13  191  14  323  15  304  16  406  Chr.    Loci 17  611  18  149  19  675  20  257  21  133  22  262  X  579  Y  44  Total number of loci: 10432

What are genetic disorders? Both environmental and genetic factors have roles in the development of any disease. A genetic disorder is a disease caused by abnormalities in an individual’s genetic material (genome).

1) Single-gene (also called Mendelian or monogenic) This type is caused by changes or mutations that occur in the DNA sequence of one gene. Genes code for proteins, the molecules that carry out most of the work, perform most life functions, and even make up the majority of cellular structures. When a gene is mutated so that its protein product can no longer carry out its normal function, a disorder can result. There are more than 6,000 known single-gene disorders, which occur in about 1 out of every 200 births. Some examples are cystic fibrosis, sickle cell anemia, Marfan syndrome, Huntington’s disease, and hereditary hemochromatosis.

Single-gene (also called Mendelian or monogenic) This type is caused by changes or mutations that occur in the DNA sequence of one gene Single-gene disorders are inherited in recognizable patterns: Autosomal dominant, Autosomal recessive, X-linked dominant, X-linked recessive,

MULTIFACTORIAL INHERITANCE The most common cause of genetic disorders is multifactorial or polygenic inheritance. Traits that are due to the combined effects of multiple genes are polygenic (many genes). When environmental factors also play a role in the development of a trait, the term multifactorial is used to refer to the additive effects of many genetic and environmental factors

(2) Multifactorial (also called complex or polygenic) This type is caused by a combination of environmental factors and mutations in multiple genes. For example, different genes that influence breast cancer susceptibility have been found on chromosomes 6, 11, 13, 14, 15, 17, and 22. Its more complicated nature makes it much more difficult to analyze than single-gene or chromosomal disorders. Some of the most common chronic disorders are multifactorial disorders. Examples include heart disease, high blood pressure, Alzheimer’s disease, arthritis, diabetes, cancer, and obesity. Multifactorial inheritance also is associated with heritable traits such as fingerprint patterns, height, eye color, and skin color.

(3) Chromosomal Chromosomes, distinct structures made up of DNA and protein, are located in the nucleus of each cell. Because chromosomes are carriers of genetic material, such abnormalities in chromosome structure as missing or extra copies or gross breaks and rejoinings (translocations), can result in disease. Some types of major chromosomal abnormalities can be detected by microscopic examination. Down syndrome or trisomy 21 is a common disorder that occurs when a person has three copies of chromosome 21.

(4) Mitochondrial This relatively rare type of genetic disorder is caused by mutations in the nonchromosomal DNA of mitochondria. Mitochondria are small round or rod-like organelles that are involved in cellular respiration and found in the cytoplasm of plant and animal cells. Each mitochondrion may contain 5 to 10 circular pieces of DNA.

NONTRADITIONAL PATTERNS OF INHERITANCE Mosaicism refers to the presence of two or more distinct cell lines This was first recognized in chromosomal disorders A newer concept is mosaicism for a gene abnormality Imprinting refers to modification of the gene as it is transmitted through the father or the mother Uniparental disomy (UPD) refers to a pair of chromosomes being inherited from one parent There are a few rare conditions due to abnormalities of mitochondrial DNA (mtDNA). Triplet repeat, unstable mutations: A triplet repeat is an unusual type of mutation in which a triplet of nucleotides increases in number within a gene

Punnett square illustrating a cross between HH and hh homozygote parents.

Punnett square illustrating a cross between two Hh heterozygotes.

Fig. 11.4, Mendel’s 7 garden pea characters.

Dihybrid cross: F1 generation

Dihybrid cross: F2 generation Ratio: 9:3:3:1

Trihybrid crosses: Involve three independently assorting character pairs. Results: 64 combinations of 8 different gametes 27 different genotypes 8 different phenotypes (2 x 2 x 2) Predicted ratio of phenotypes = 27:9:9:9:3:3:31

Summary of Mendel’s Principles: Mendel’s Principle of Uniformity in F1: F1 offspring of a monohybrid cross of true-breeding strains resemble only one of the parents. Why? Smooth seeds (allele S) are completely dominant to wrinkled seeds (allele s). Mendel’s Principle of Segregation: Recessive characters masked in the F1 progeny of two true-breeding strains, reappear in a specific proportion of the F2 progeny. Two members of a gene pair segregate (separate) from each other during the formation of gametes. Inheritance is particulate, not blending as previously believed. Mendel’s Principle of Independent Assortment: Alleles for different traits assort independently of one another. Genes on different chromosomes behave independently in gamete production.

Rediscovery of Mendel’s Principles: William Bateson (1902)-experiments with fowl first demonstrated that Mendel’s principles applied to animals. Bateson argued that mutation (not selection) was the most important force shaping variation in plants and animals. William Bateson also coined the terms: Genetics Zygote F1 F2 Allelemorph ( allele) 1907 - Reginald Punnett and William Bateson

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