Chapter 16: Human Genetics and the Human Genome

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Studying Human Genetics

• Studies of an individual’s karyotype, the number and kinds of chromosomes present in the nucleus, enable researchers to identify various chromosome abnormalities.
• A pedigree is a “family tree” that shows the transmission of genetic traits within a family over several generations.
  • Pedigree analysis is useful in detecting autosomal dominant mutations, autosomal recessive mutations, X-linked recessive mutations, and defects due to genomic imprinting, which is the expression of a gene based on its parental origin.
• The database of the Human Genome Project contains the entire sequence of human chromosomal DNA.
  • Large international collaborative efforts such as the 1000 Genomes Project and the ENCODE Project have allowed investigators to construct maps of the human genome showing the location of natural variations in DNA in human populations, such as single nucleotide polymorphisms (SNPs), and the locations of DNA sequences involved in biological functions.
  • Researchers use these polymorphisms in genome-wide association (GWAS) studies to identify genetic variations associated with complex human diseases.
  • Investigators then use gene database information to identify affected genes and understand the role of each gene, how each gene interacts with other genes, and how the expression of each gene is regulated in different tissues.
  • Comparative genomics examines the relationships among genes, genomic structures, and functions among different species.
  • The identification of genes and genomic regions in other species that are highly conserved with those in humans allows investigators to study their structure and function in model organisms such as the mouse, Drosophila, C. elegans, yeast and E. coli.
  • These studies provide important insights into the roles of those genes in humans.

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Abnormalities in Chromosome Number and Structure

• In aneuploidy there are either missing or extra copies of certain chromosomes.
  • Aneuploidies include trisomy, in which an individual’s cells contain an extra chromosome, and monosomy, in which one member of a pair of chromosomes is missing.
• Trisomy 21, the most common form of Down syndrome, and Klinefelter syndrome (XXY) are examples of trisomy.
  • Turner syndrome (X0) is an example of monosomy.
• Trisomy and monosomy are caused by meiotic nondisjunction, in which sister chromatids or homologous chromosomes fail to move apart properly during meiosis.
• In a translocation part of one chromosome becomes attached to another.
  • About 4% of individuals with Down syndrome have a translocation in which the long arm of chromosome 21 is attached to the long arm of one of the larger chromosomes, such as chromosome 14.
• A deletion can result in chromosome breaks that fail to rejoin.
  • The deletion may range in size from a few base pairs to an entire chromosome arm.
  • One deletion disorder in humans is cri du chat syndrome, in which part of the short arm of chromosome 5 is deleted.
• Fragile sites may occur at specific locations on both chromatids of a chromosome.
  • In fragile X syndrome, a fragile site occurs near the tip on the X chromosome, where the nucleotide triplet CGG is repeated many more times than is normal.
  • Fragile X syndrome is the most common cause of inherited intellectual disability.
• Genomic imprinting can affect the expression of a gene based on its parental origin.
  • An allele can be repressed or expressed, without any changes to the DNA base sequence, depending on the parent from which it was inherited.

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Genetic Diseases Caused by Single-Gene Mutations

• Most human genetic diseases that show a simple inheritance pattern are transmitted as autosomal recessive traits.
• Phenylketonuria (PKU) is an autosomal recessive disorder in which toxic phenylketones damage the developing nervous system.
  • Sickle cell anemia is an autosomal recessive disorder in which abnormal hemoglobin (the protein that transports oxygen in the blood) is produced.
  • Cystic fibrosis is an auto- somal recessive disorder in which abnormal secretions are produced primarily in organs of the respiratory and digestive systems.
  • Tay-Sachs disease is an autosomal recessive disorder caused by abnormal lipid metabolism in the brain.
• Huntington’s disease has an autosomal dominant inheritance pattern and results in mental and physical deterioration, usually beginning in adulthood.
• Hemophilia is an X-linked recessive disorder that results in a defect in a blood component required for clotting.

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Gene Therapy

• In gene therapy the normal allele is cloned, and the DNA is introduced into certain human cells where its expression may be sufficient to yield a normal phenotype.
• One technical challenge in gene therapy is finding a safe, effective vector, usually a virus, to deliver the gene of interest into the cells.

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Genetic Testing and Counseling

• In amniocentesis a physician samples the amniotic fluid surrounding the fetus and then cultures and screens the fetal cells suspended in the fluid for genetic defects.
  • Amniocentesis provides results in the second trimester of pregnancy.
• In chorionic villus sampling (CVS), a physician removes and studies some of the fetal cells.
  • CVS provides results in the first trimester of pregnancy but is associated with a slightly greater risk of infection and miscarriage than amniocentesis.
• Couples who conceive by in vitro fertilization may elect to have preimplantation genetic diagnosis (PGD), in which a physician screens the embryos for one or more genetic diseases before placing a healthy embryo into the woman’s uterus.
  • PGD is not as accurate as amniocentesis or CVS, and it is more expensive.
• Genetic screening identifies individuals who might carry a serious genetic disease.
  • Screening of newborns is the first step in preventive medicine, and screening of adults helps them make informed reproductive decisions.
• Couples who are concerned about the risk of abnormality in their children may seek genetic counseling.
  • A genetic counselor provides medical and genetic information pertaining to reproductive decisions and helps individuals understand their situation and avoid feeling stigmatized.

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Human Genetics, Society, and Ethics

• Genetic discrimination is discrimination against an individual or family member because of differences from the “normal” genome in that individual.
• One of the most difficult issues in avoiding genetic discrimination is whether genetic information should be available to employers and to health and life insurance companies.
  • The Genetic Information Nondiscrimination Act (GINA) prohibits employers and insurance companies from discriminating on the basis of information derived from genetic tests.

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