Mutations Gene mutations occur within a gene and result in a change in the nucleotide sequence. Chromosomal mutations affect all or part of a chromosome. Two types of chromosomal mutations: –Structural –Numerical

The collection of all the chromosomes is referred to as a Karyotype: Human Karyotype as shown by traditional chromosome banding. The chromosomes are defined by size, position of the centromere and location of the stained bands.

Prenatal diagnosis: amniocentesis sampling cells from amniotic fluid usually done ~ weeks

Preparing a karyotype harvest cells culture cells 1-2 days arrest cells in metaphase with colchicine “spread” cells on slide and stain count chromosomes in 20 representative cells capture image of 5 “best” cells and construct karyotypes for each metaphase

Pair homologous chromosomes and cut out images.

Completed normal human karyotype

Abnormal karyotype

Nondisjunction occurs when problems with the meiotic spindle cause errors in daughter cells. –This may occur if tetrad chromosomes do not separate properly during meiosis I. –Alternatively, sister chromatids may fail to separate during meiosis II. 1. Alterations of chromosome number some genetic disorders Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings Fig

MEIOSIS I NONDISJUNCTION

MEIOSIS II NONDISJUNCTION

As a consequence of nondisjunction, some gametes receive two of the same type of chromosome and another gamete receives no copy. Offspring results from fertilization of a normal gamete with one after nondisjunction will have an abnormal chromosome number or aneuploidy. Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings

Types of aneuploidy –Monosomic cells have only one copy of a particular chromosome type and have 2n - 1 chromosomes. (Turner’s syndrome: X0) –Trisomic cells have three copies of a particular chromosome type and have 2n + 1 total chromosomes. (Down Syndrome: 3 chromosome 21’s) If the organism survives, aneuploidy typically leads to a distinct phenotype.

SYNDROMES ASSOCIATED WITH ANEUPLOIDY OF AUTOSOMAL CHROMOSOMES

Down syndrome, is due to three copies of chromosome 21. It affects one in 700 children born in the United States. Although chromosome 21 is the smallest human chromosome, it severely alters an individual’s phenotype in specific ways.

Down Syndrome Features Brushfield spots Upslanting palpebral fissures Epicanthic folds Flat nasal bridge Single Palmar (simian) Crease Short broad hands 5 th finger clinodactyly

Potter’s Atlas of Fetal and Infant Pathology, 1998 Trisomy 18 Phenotype Very Hypertonic – note contractures

Trisomy 18 Phenotype Characteristic Clenched Hands Short sternum Cardiac Anomalies Single umbilical artery

Rocker Bottom Feet in +18

Trisomy 13 (Patau) Syndrome 47,XY,+13 Severe mental retardation Physical abnormalities

Trisomy 13 Phenotype Craniofacial anomalies –Sloping forehead –Cleft lip and palate –Bulbous nose –Micropthalmia – very small eyes Holoprosencephaly Microcephaly

See polydactyly and very malformed ears

Nondisjunction of sex chromosomes produces a variety of aneuploid conditions in humans. Unlike autosomes, this aneuploidy upsets the genetic balance less severely. –This may be because the Y chromosome contains relatively few genes. –Also, extra copies of the X chromosome become inactivated as Barr bodies in somatic cells. Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings

Klinefelter’s syndrome, an XXY male, occurs once in every 2000 live births. –These individuals have male sex organs, but are sterile. –There may be feminine characteristics –Their intelligence is normal. Males with an extra Y chromosome (XYY) tend to somewhat taller than average. Trisomy X (XXX), which occurs once in every 2000 live births, produces healthy females. Monosomy X or Turner’s syndrome (X0), which occurs once in every 5000 births, produces phenotypic, but immature females. Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings

Jacobs Syndrome-caused by nondisjunction of the Y chromosome during the second phase of meiosis giving a 47 XYY karyotype. Occurence is 1/1000 live male births. Men with this karyotype are tall and have low mental ability.

Organisms with more than two complete sets of chromosomes, have undergone polypoidy. This may occur when a normal gamete fertilizes another gamete in which there has been nondisjunction of all its chromosomes. –The resulting zygote would be triploid (3n). Alternatively, if a 2n zygote failed to divide after replicating its chromosomes, a tetraploid (4n) embryo would result from subsequent successful cycles of mitosis. Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings

Polyploidy has been induced in certain plants that have become major food crops. EX. Wheat, Corn, Strawberries.

Structural Chromosomal Mutations Breakage of a chromosome can lead to four types of changes in chromosome structure. –Deletion –Duplication –Inversion –Translocation

A deletion occurs when a chromosome fragment lacking a centromere is lost during cell division. –This chromosome will be missing certain genes. A duplication occurs when a fragment becomes attached as an extra segment to a sister chromatid.

46,XY,der(8)t(8;9)(q24.3;q22.1) partial trisomy or duplication due to 2:2 segregation

46,XY,der(9)t(8;9)(q24.3;q22.1) partial monosomy or deletion

An inversion occurs when a chromosomal fragment reattaches to the original chromosome but in the reverse orientation. In translocation, a chromosomal fragment joins a nonhomologous chromosome. –Some translocations are reciprocal, others are not. Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings Fig c & d

46,XY,t(8;9)(q24.3;q22.1)

Chromosomal translocations between nonhomologous chromosomes are also associated with human disorders. Chromosomal translocations have been implicated in certain cancers, including chronic myelogenous leukemia (CML). –CML occurs when a fragment of chromosome 22 switches places with a small fragment from the tip of chromosome 9. Some individuals with Down syndrome have the normal number of chromosomes but have all or part of a third chromosome 21 attached to another chromosome by translocation. Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings

Chronic myelogenous leukemia

abl/bcr Genes on Diploid Cells and Ph Positive CML Cells

Not all of a eukaryote cell’s genes are located in the nucleus. Extranuclear genes are found on small circles of DNA in mitochondria and chloroplasts. These organelles reproduce themselves. Their cytoplasmic genes do not display Mendelian inheritance. –They are not distributed to offspring during meiosis. Extranuclear genes exhibit a non- Mendelian pattern of inheritance Copyright © 2002 Pearson Education, Inc., publishing as Benjamin Cummings