Biology CH13 The chromosomal basis of Inheritance and human genetics

MCGhill

Chromosomal Theory of inheritance, Carl Correns lived during

1900

Chromosomal Theory of inheritance, Carl Correns first suggests

Central role for Chromosomes

Chromosomal Theory of inheritance, Carl Correns Authored one of the scientific papers announcing

Rediscovery of mendel’s work

Chromosomal Theory of inheritance, Walter Sutton lived durring  

1902

Chromosomal Theory of inheritance, Walter Sutton known for

Chromosomal theory of inheritance

Chromosomal Theory of inheritance, Walter Sutton Based on observation that 

Similar chromosomes Paired with one another during meiosis 

Inheritance of eye color in fruit flies, image

Inheritance of eye of color in fruit flies, T.H. Morgan lived

1910

worked with fruit flys

Discovered a mutant male fly with white eyes instead of red

crossed the mutant male with normal red eye female, all F1 progeny red eyed dominant trait

The eye color Gene resides on the X chromosome,

Morgan crossed 

F1 females x F1 males

The eye color Gene resides on the X chromosome,

F2 generation contained

Red and white eyed flies

but all white eyed flies were male

The eye color Gene resides on the X chromosome,

Testcross of a F1 female with a white eyed showed 

The viability of white eyed females 

The eye color Gene resides on the X chromosome,

Morgan concluded that the eye color Gene resides on the

Females X Chromosomes

The eye color Gene resides on the X chromosome,

Traits determined by

sex chromosomes genes are sex linked

Sex chromosmomes,

Sex chromosomes are a pair of dissimilar

chromosomes that still pair during meiosis and mitosis

Sex chromosomes

Sex determination in Drosophila is based on the

Number of X chromosomes

2 X chromosomes = female

1X and 1 Y chromosomes = male

Chromosomal basis of X linkage, Figure 

Sex Determination, 

sex determination varies 

Across Organisms

Sex determination,

Is based on presence of a

Y chromosomes in Humans

2 X= female

Having a Y chromosomes (XY) = male

Sex determination

in birds

ZZ = Male

WW = female

Sex determination,

In insects are

XX= female

OX= male

O is indicating of absent or missing chromosomes

Sex Determination in some organisms, Table 

Sex Chromosomes in humans,

Humans have total 46 chromosomes 

22 pairs are autosomes, non sex chromosomes

1 pair of sex chromosome highly condensed

Y chromosomes highly condensed, recessive alleles on male’s X have no active counterpart on Y 

Default for humans is female, requires SRY gene on Y for Malesness

sex chromosomes in human, image

Sex linkage,

In organisms with XY SEX determination ( like Humans)

Few genes form Y chromosomes are expressed

Sex linkage,

Result is that recessive alleles on X chromosomes have no 

Active partner on Y therefore a single recessive sex linked gene can produce recessive phenotype 

Sex linkage,

Certain genetic disease affect males to a 

Grater degree than females as a result 

Sex linkage

X linked recessive alleles

Red green color blindness

Hemophilia

Dosage Compensation,

Ensures equal expression of genes form sex chromosomes even though

Number of chromosomes is different between sexes

Dosage Compensation,

In mammalian female cells

1 X chromosomes is randomly Inactivated is highly condensed into a Barr body

Dosage compensation,

Female Heterozygous for genes on the

X chromosomes are genetic Mosaics,

Example: Calico Cat

Calico cat, Image

Chromosome theory exceptions,

Mitochondria and Chloroplasts

Contain genes

Chromosomes theory exceptions,

Traits controlled by these genes do not follow the

Chromosomal theory of inheritance

Chromosome theory exceptions,

Genes form Mitochondria and chloroplasts are often passed to the offspring by 

Only one parent often the mother called, Maternal inheritance

Chromosome theory exceptions,

In plants chloroplasts are also often inherited form the 

Mother although this is species dependent 

Genomic imprinting,

In genomic imprinting the phenotype exhibited by a mutant allele depends on

Which parent contributed the allele to the offspring

Genomic Imprinting,

Specific partial deletion of chromosomes 15 in humans results in

Angleman syndrome if form the mother

Prayer Wili syndrome if the chromosome is form the father

the mouse igf 2 gene

Insulin like growth factor 2 (igf)

Encodes a growth factor critical for preatal development and growth

only paternal allele is expressed, phenotype of herterozygotes depend on which parent contributed the mutant allele

Epigenetics,

Imprinting is an example of epigenetics, Epignetics inheritance

A Mitotically and or meiotically stable change in gene function that dose not involve a change in DNA sequance

Epigenetics,

Mechanisms

DNA, Methylation and Histone Modification

Non coding RNA’s

Nuclear Organization

Alterations to proteins involved in chromosome a structure

Genetic Mapping,

Early genetics realized that they could obtain information about the

distance between genes on a chromosome

Genetic Mapping,

Distance estimates based on patterns of

Genetic recombination (crossing over) between genes

Genetic mapping, if crossover occurs, parental alleles are

Recombinded producing recombinant gametes

Crossing over exchanges alleles, Diagram

Recombination is the basis for genetic maps,

Alfred Sturtevant

Undergraduate in T.H. Morgan lab

Put morgans observation that recombinant progeny reflect relevant location of genes in quantitative terms

As physical distance on a chromosome increase so dose the probability of recombination (cross over) Occuring between the gene loci

Construction maps,

The distance between genes is proportional to the

Frequency of Recombination events

Recombination Frequency equation 

Recombination frequency= recombinat progency/ total progeny 

construction maps,

1% recombination =

1 map unit (m.u.)

Construction Maps

1 map unit= 

1 centimorgan (cM)

Construction Maps

Preformane testcross with 

Doubly heterozygous individuals, count progeny 

two point cross to map genes, Diagram

Multiple crossover

If homologues undergo two crossover

Between loci, then the parental combination is restored

Multiple crossovers

leads to an underestimate of the 

True genetic distance

odd number of cross over events (1,3, ect.) produce recombination gametes 

No cross over or even numbers of cross overs (0,2,4, ect) produce parental gametes

Multiple crossover

Relationship between true distance on a

Chromosome and the recombination frequency is not linear

Relationship between true distance and recombination frequency, Graph

Three point testcross

Uses 

Three loci instead of two to construct maps

Three point testcross

Middle gene allows tracking of

Recombination events on either side

Three points testcross

In any three point cross the

class of offspring with two crossovers is the least frequent class

Three point test cross

In practice geneticists use three point crosses to determine the 

Order of genes then use data form the closest two point crosses to determine distances 

three point cross to order genes, diagram

Some human traits exhibit domain/ recessive inheritance

Some human traits are controlled by

A single gene

some of these exhibit dominant and recessive inheritance

Some human traits exhibit domain/ recessive inheritance

pedigree analysis is used to 

Track inheritance patterns in families 

Some human traits exhibit domain/ recessive inheritance

Dominant pedigree example

Juvinile glaucoma

Some human traits exhibit domain/ recessive inheritance

Recessive pedigree example

Albinism

Dominant pedigree for hereditary juvenile glaucoma

Disease causes degeneration of optic nerve leading to blindness

Dominant trait appears in every generation 

Dominant pedigree for hereditary juvenile glaucoma

Recessive Pedigree for albinism

Condition in which the pigment melanin is not produced

From of albinism due to a nonfunctional allele of the enzyme tyrosinase

males and females affected equally

most affected individuals have unaffected parents

Recessive Pedigree for albinism

Sex linked human genetic disorders,

some genetic disorders affect

Males more than females

this is sex linked

Sex linked human genetic disorders,

Hemophilia is a disease that affects a

Single proteins in a cascade involved in formation of blood clots

Sex linked human genetic disorders,

form the hemophilia is cuased by an

X linked recessive alleles,

Heterozygous females are asymptomatic carriers

Human genetic disorders causes,

a single amino acid change in a

Single protein can result in clinical syndrome

Human genetic disorders causes,

Example: Sickle cells anemia

First human disease shown to be result of mutation in a protein

Cuased by a defect in the oxygen carrier molecule hemoglobin

Leads to impaired oxygen delivery to tissue

Sickle cell anemia, image

Sickle cell aniemia,

Homozygotes for sickle cell allele

Exhibit intermettent illness and reduced life span

Sickle cell anemia

Heterozygotes  appear

Normal

Do have hemoglobin with reduced ability

Sickle cell anemia

Sickle cell allele is particularly prevalent in

People of African descent

Proportion of heterozygotes higher than expected

Confers resistance to blood borne parasite that causes malaria, explains higher proportion of allele

Some important genetic disorders, Table

Nondisjunction changes chromosome Number

Nondisjunction is the failure for

Homologuse or sister chromatids to separate properly during meiosis

Nondisjunction changes chromosome number,

Aneuploidy

Gain or loss of chromosomes the result of nondisjunction

Monosomy or Trisomy, in all but a few cases do not survive

Aneuploidy

Monosomy

Loss

Aneuploidy

Trisomy

Gain

Nondisjunction of autosomes

Human embryos Trisomic for five of the

Smallest autosomes can survive birth


Autosomes: 13, 15, 18, 21, and 22

13, 15, 18- sever defects, die within a few months

21 and 22- can survive to adulthood

down syndrome- Trisomy 21, my be full third 21st chromosome, a translocation of part of chromosomes 21, mothers age influences risk

Trisomy of chromosome 21

Correlation between maternal age and incidence of down syndrome, 

Graph 

Nondisjunction of Sex Chromosomes

Do not generally experiacnce severy development abnormalities

Individuals have somewhat abnormal features but often reach maturity and in some cases may be fertile

XXX- triple females

XXY- males ( Klinefelter syndrome)

XO- females (Turner Syndrome)

OY- Non viable zygotes

XYY-males ( Jacob syndrome)

Nondisjunction and sex chromosomes, Diagram

Some genetic defects can be detected early in pregnacy

Genetic counseling can help identify parents

Carrying disease alleles and asses genetic state of early embryos

Pedigree analysis used to determine the probability of genetic disorders in the offspring

Aminocentesis collect fetal cells form the aminotic fluid for examination

Chorinic villi sampling (CVS) collects cells form the placenta for examination

Amniocentesis

Chorionic Villus Sampling

Human Genome Maps

Cannot use techniques from model systems

For example inducing and tracking mutations, to create human genome maps

Human Genome Maps 

Can use data derived form

Historical Pedigrees

Human Genome Maps

Difficult analysis

Number of markers was not denes enough for mapping up to 1980s

Disease cuasing ( that is tracible) alleles are rare

Human Genome Maps

Situation changed with the

development of anonymous Markers

Detected using molecular techniques

No detectable phenotype

Molecular markers

Alternative to mutant/disease alleles some

Molecular marks are identifiable via modern genetic techniques and do not alter phenotype

Short tandem repeats (STR) are short repeats of 2-4 bases that can differ in repeat number between individuals 

Single neucleotide polymorphism (SNPs) affect a single base of a gene locus 

More than 600 million SNPs identified in human genome 

Used in forensic analysis to ID suspects or for paternity testing

The Human X Chromosomes Gene Map 

Diagram 

Genetic maps and genetic disorders

Human genetic maps can be constructed using common genetic markers

Data form related individuals is used instead of data form controlled crosses as in model organisms

Analysis requires complex statistical analysis and large amounts of data

Genetic maps and genetic disorders

Tracking the segregation of possible causal alleles with a disorder

phenotype across multiple families can localize the disorder alleles on the genome

Example: cystic fibrosis (Recessive allele), Hunting tone disease (Dominant allele)

Phenotype to genotype association studies 

Many common disease are quantitative traits, affected by

Many genes that require different techniques to discover underlying genes

Phenotype to Genotype association studies

Genome wide association study (GWAS) looks for SNPs associated with a

disease Phenotype as likely regions of genome where candidate genes are located

Requires large amounts of population level data and is computationally intensive