Genetic control of inheritance, congenital anomalies, single-gene abnormalities, chromosomal abnormalities, non-disjunction disorders, X-inactivation, translocation disorders, mitochondrial inheritance

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Colorado State University
Biomedical Science
BMS 460
D.Rao Veeramachaneni

28 August Basics in Genetic Control of Inheritance Genetic information is stored on chromosomes, of which there are 23 pairs in each human cell. 22 pairs are autosomes, and they are numbered when arranged by size and shape in a diagnostic graphic termed a karyotype. The 23 pair consists of the pair of sex chromosomes; males have XY, and females have XX. Short arm: p (petite) Long arm: q The chromosomes are made up of many genes, which are matched for a function (allele) at a specific location on the paired chromosomes. All cells in an individual’s body contain the same chromosomes and genes for the same traits (genotype), although not all genes are active in each cell. When a specific gene for a pathologic condition is identified, a DNA analysis follows with the hope for the development of a simple blood test to screen individuals for the presence of that specific gene. During meiosis (gametogenesis), each human sperm and ovum receive only 23 chromosomes, that is, one chromosome from each pair (haploid). When the ovum is fertilized by the sperm, the resulting zygote has 46 chromosomes, or 23 pairs (diploid) containing an assortment of genetic information inherited from the parents. During embryonic and fetal development, when cells undergo mitosis, the chromosomes replicate, and each daughter cell receives a copy of DNA identical to that in the parent cell carrying forward the same genetic information. Rapid Whole-Genome Sequencing for Genetic Disease Diagnosis in Neonatal Intensive Care Units Infant DNA tests speed diagnosis of rare diseases About one in 20 babies in newborn intensive care units has a genetic disease, and all too often, no one can figure out what it is. Scientists identified the faulty genes for about 3,500 of 7,500 known genetic diseases; about 500 have treatments. With the new method, a computer program searches for genes based on the baby’s symptoms. And because it focuses only on genes that cause diseases in newborns, it avoids an ethical problem: findings that are unrelated to the problem at hand. In sequencing and analyzing the entire DNA, researchers may discover, for example, aberrations leading to conditions that occur only in adults. The method is expensive, though, costing about $13,500. It is not yet covered by insurance. It should be cost effective for insures as each day a baby spends in intensive care costs about $8,000, so any test that reduces that time would quickly pay for itself. A close look at how gametes form Meiosis Diploid cell DNA replication Homologous chromosome pairing Meiosis I: crossing over and random distribution of chromosomes during the first meiotic division contribute to the enormous genetic variability of the daughter cells Meiosis II: works as mitosis Four haploid cells Compare to mitosis Diploid cell DNA replication Mitosis: chromosomes line up in center, pulled to ends Two diploid cells Congenital anomalies refer to disorders present at birth Such defects include genetic or inherited disorders as well as developmental disorders (often do not have a genetic component) Genetic changes can occur because of an error in the process of meiosis or mitosis. Such a mutation or alteration in genetic material – e.g. transition, transversion, deletion, substitution – may occur Spontaneously or May result from exposure to harmful substances such as radiation, chemicals, or drugs Genetic disorders may result from A single-gene trait or A chromosomal defect (numerical and/or structural) or Polygenic traits Polygenic traits are determined by multiple genes located on more or more chromosomes E.g., eye color, finger prints Multifactorial events Multifactorial inheritance represents the additive effects of many abnormal genes and environmental factors Multifactorial disorders tend to run in the families E.g., obesity, hypertension, atherosclerosis, diabetes Single-gene Abnormalities Autosomal dominant diseases usually affect structural proteins and receptors whereas many autosomal recessive gene disorders involve an enzyme deficit Mutations of single genes in the body cells other than the reproductive cells may cause dysfunction but are not transmitted to offspring. In some cases, the expression, or effect (phenotype), of an altered gene produces clinical signs that vary in severity depending on the penetration or activity of the gene. Single-gene disorders are caused by a change in one gene within the reproductive cells (sperm or ova); this mutant gene is then transmitted to subsequent generation, following the specific inheritance pattern for that gene. Mendelian traits (single gene defects) reflect the expression of two copies (alleles) of the same gene present on homologous chromosomes. Mendelian traits may be caused by the inheritance of one or both defective alleles, depending on the nature of the gene product. The most important forms of Mendelian inheritance are Autosomal dominant traits require the expression of only one allele of a homologous pair (i.e., the phenotype is present when alleles are heterozygous or homozygous.) E.g. familial hypercholesterolemia, adult polycystic kidney disease, hereditary elliptocytosis and spherocytosis, neurofibromatosis type I, Ehlers-Danlos syndrome, von Willebrand disease, familial adenomatous polyposis coli, Marfan syndrome, osteogenesis imperfecta, achondroplasia Autosomal recessive traits require the expression of both alleles of a homologous pair (i.e., the phenotype is present when alleles are homozygous [similar]) E.g. sickle cell anemia, thalassemia, hereditary hemochromatosis, Gaucher disease, myeloperoxidase deficiency, cystic fibrosis Sex-linked traits Sex-linked recessive traits are most commonly seen in heterozygous males (46, XY) who lack the matching normal gene on Y. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. X-linked recessive disorders require the expression of both alleles on the X- chromosome (i.e., the phenotype is present in females only when X-linked alleles are homozygous [In heterozygotes, random X-inactivation results in mosaics leading to variable phenotypic manifestations.]) E.g. Duchenne-Becker muscular dystrophy, Hemophilia A (factor VIII deficiency), Lesch-Nyhan syndrome (HPRT deficiency), color blindness X-linked dominant disorders affect both males and females E.g. fragile X syndrome, the most common cause of learning disorders, cognitive deficit and mental retardation in North America. The mutation causes the affected X chromosome to appear constricted or broken. X-Inactivation and Dosage Compensation Given that mammalian females have two X chromosomes and males one, humans and most other mammals have evolved a means of dosage compensation to correct for the expected effect of 2 X chromosomes vs. one. One X becomes inactive (not totally) – Barr body X-inactivation is random In any cell, initial inactivation (at blastocyst stage) may affect either the X transmitted by the father or the X from the mother. The pattern is then fixed and is passed on to all daughter cells throughout mitosis and development; thus females are mosaics regarding X-linked gene expression. This biologic mosaicism has important impacts on phenotypic expression for X- linked traits in heterozygous females. Chromosomal Abnormalities Numerical or structural abnormalities of autosomes or sex chromosomes Chromosomal anomalies usually result from an error during meiosis When the DNA fragments are displaced or lost, thus altering genetic information, e.g., a form of Down syndrome. This may be spontaneous or result from exposure to a damaging substance.
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