Genetics

Chromosomes

Chromatid

Chromatid

Centromere↓

Karyotype – spread of human chromosomes to look for chromosomal abnormalities

OROR

Chromosome Terminology Homologous Chromosomes – paired

chromosomes – same size, same banding pattern, same type of genes but not necessarily the exact same forms of each gene Example – gene on one chromosome for

brown eyes and gene on its homologue for blue eyes

GGGTCAGTCATTTTAAGAGATC

GGGAAAGTCATTTTAAGAGATC

Remember – Sister Chromatids are two halves of the same double chromosome and are exact copies of one another

Real Karyotype

Down’s Syndrome Karyotype

Cell Types Diploid – cell with the normal # of

chromosomes (2n) Haploid – cell with ½ the normal

number of chromosomes (n) Somatic cell – normal body cell Sex Cell, gamete – sperm and egg

– haploid cells Germ cell – 2n cell that is the

precursor to the gametes

Meiosis – cell division process that produces the sperm and egg (n)

Purpose of Meiosis To make haploid sex cells so that

when they come together, the zygote has the normal amount of DNA (2n)

EggEgg

nn

SpermSperm

nn

ZygoteZygote

2n2n

FertilizationFertilization

→→MitosisMitosis

EmbryoEmbryo

Steps of Meiosis

Chromosomes form and homologous pairs come together

Germ Cell (2n) in G1 (46 single chromosomes)

S-Phase – copy all DNA so after have 46 double chromosomes

When Chromosomes form in meiosis I – 46 doubles

Crossing over in Prophase I

Homologous Pairs line up down center

Still 46 doubles or

23 double pairs

Each daughter cell has 23 double chromosomes – no longer have pairs – just one of each pair

Meiosis I is the reduction division because the cell went from 46 chromosomes or 23 pairs to just 23 chromosomes

The daughter cells are now haploid but they don’t yet have ½ of the DNA of the orginial germ cell, they must undergo meiosis II

Chromosomes reform in the two daughter cells

Each individual chromosome lines up down the center and sister chromatids split

Now that sister chromatids split – we have 23 single chromosomes – ½ the DNA of a normal cell – this is the finished sex cell

Summary

Meiosis happens only in ovaries and testes to make sperm and egg

Sperm and egg have only 1 of each pair of chromosomes and are haploid

Sex cells come together to make a zygote that contains a pair of each chromosomes again and is diploid

Mitosis vs. Meiosis

Egg vs. Sperm

Germ cell = spermatogonium (undergo mitosis and one daughter cell goes thru meiosis)

Primary Spermatocyte – Prophase I

↓ meiosis I Secondary Spermatocyte –

haploid

↓ meiosis II

Spermatids Sperm (grow tails and

head changes shape)

Germ cell = oogonium (undergo mitosis and one daughter cell goes thru meiosis)

Primary oocyte (Prophase I) (frozen in metaphase I)

↓ meiosis I (hormone stim.)

Secondary oocyte (haploid) and 1 polar body (frozen in met II)

↓ meiosis II (stimulated by fert.)

Oocyte + 2nd polar body

Sexual Reproduction Brings about Variation by: Crossing Over Independent Assortment

Amount of variation due to IA – 2n

In humans = 2 23 = 8 million Random Fertilization

8 million x 8 million = 64 trillion combinations

Crossing Over makes this almost infinite

Chromosomal Abnormalities Trisomy or Monosomy due to

non-disjunction during meiosis Chromosomal deletions (a

piece of a chromosome breaks off)

Chromosomal Translocations (whole or parts of chromosomes)

Chromosomal Inversions

Non-disjunction causes trisomy’s, monosomy’s, and

aneuploidy

Chromosomal Abnormalities

Translocation of chromosome 13 and 14 – normal phenotype

Translocation Abnormality Philadelphia Chromosome

A piece of chromosome 22 is translocated to chromosome 9 causing Chronic Myelogenous Leukemia

Chromosomal Deletions

Each chromosome 22 on the right of each pair is missing a piece

Cri-du-chat – have a deletion from chromosome #5 and the babies sound like a cat crying – mental retardation and heart disease

Mendelian Principles Alleles – different forms of the

same gene Dominant – gene that is seen Recessive – only seen if with

another recessive allele Homozygous – having 2 like alleles Heterozygous – having 2 different

alleles Genotypes – actual gene make-up

for a particular locus or trait Phenotypes – visible trait

Mendelian Laws

Law of SegregationLaw of Segregation - When the gametes form – each gamete receives only 1 of each pair of alleles.

Law of Independent AssortmentLaw of Independent Assortment – If genes aren’t on the same chromosome (linked) they will not have to remain together in the gamete - if they are linked, they will sometimes assort independently due to crossing over

Punett Squares – Mono and Di-Hybrid Crosses

Used to calculate the probability of Used to calculate the probability of having certain traits in offspringhaving certain traits in offspring

Figure out all possible gametes for male and females

Place them on the outside of the square

Cross the gametes to come up with the possible genotypes and phenotypes of the offspring

Using Probability to Calculate Offspring Outcomes Rather than

Punnett SquaresMultiplyMultiply – when 2 things must happen independently in order to get the outcome (and)

AddAdd – when either of two things can happen to get an outcome. (or)

Examples: RrYy x RrYy

Chance of getting an rryy offspring?

Chance of getting an RrYr offspring?

Beyond Mendel Incomplete Dominance – the phenotype

in the heterozygous condition is a mix of the two (white and red snapdragons make pink)

Co-dominance – both alleles are expressed in heterozygous condition (A,B blood types, Roan cattle)

This can become a “gray” area in diseases – Tay Sachs – make ½ normal protein and ½ misshapen – do not exhibit disease so recessive but molecularly have both expressed so is it co-dominance or even incomplete if has a slight effect ????

Multiple Alleles

More than two allele choices although always only have 2 alleles at each gene locus

Example: Human Blood TypesAlleles = A, B, & O (also an example of co-dominance)

Paternity Testing?

Sex-Linked

Located on a sex chromosome Usually is X-linked (few known

genes on the Y) X-linked usually show more in

males since only have 1 allele – only need 1 recessive allele to show

Pedigrees Used to figure out genotypes of

family members to see if someone is carrying a disease gene

Used to determine the mode of inheritance

Practice

Pedigree for Hemophilia

Genetics Plays a Role in HistoryQueen Victoria’s daughter, Alice, married a German prince, Louis, and converted to Lutheranism. Their daughter, Queen Victoria’s granddaughter, Alexandra was, thus, a German princess, grew up in Germany, and was raised in the Lutheran church. Alexandra, married Tsar Nicholas, the last tsar of Russia, and they had four daughters: Olga, Tatiana, Marie, and Anastasia. Many people in Russia didn’t like Tsarina Alexandra because she was German, not Russian, and Lutheran, not Russian Orthodox. Her mannerisms, speech, and dress were not what many people in Russia thought of as appropriate for the Tsar’s wife. Also, in Russia at that time, only a male could be tsar, so unless Alexandra and Nicholas had a son, the leadership would pass to another of Nicholas’ relatives when he died. Finally, however, they had a son who they named Alexei. Unfortunately, however, they soon discovered that he had inherited the hemophilia allele from Alexandra, from Alice, and from Queen Victoria. Realizing that chances were very slim that Alexei would survive to adulthood, Tsar Nicholas and his family became very withdrawn to try to keep that a secret (Alexandra was not very outgoing, anyway, which the people didn’t like). However, at that time, there was much social unrest in Russia, and the general public mistook the royal family’s withdrawl for aloofness and as a sign that they didn’t care about the poor living conditions of their people. Thus, Alexei’s hemophilia was probably a major contributing factor in the Russian revolution. On several occasions, Alexei had severe internal bleeding, and a rather disreputable man named Rasputin was somehow able to stop the bleeding. Because of his inexplicable ability to help Alexei, Rasputin became part of the “inner circle” and close confidant of the royal family, which also angered many people who did not trust him.Thus, when the Russian Revolution began, Rasputin was among the first to be executed. Eventually, Tsar Nicholas and his family were put under house arrest in Siberia. On 18 June 1918, Anastasia, the youngest of the daughters, turned 17 while the family was still under house arrest, and about a month later, just after midnight on 16 July, the royal family and several of their servants were all ordered down into the basement of the house, and the soldiers who had been guarding them shot and killed them all. Then, their remains were taken out of town, burned in a bonfire, then buried, together, in an unmarked grave. For years, no one knew where that grave was until, when Communist rule ended, records became available. In 1991, what was thought to, perhaps, be that grave was found, the bones were carefully removed, and as much as possible, the skeletons were reconstructed. Through the use of modern DNA technology, DNA samples from the bones were compared to DNA from the Tsar’s brother’s body (buried in a crypt in a church in St. Petersburg) and to DNA from someone in the English royal family. On that basis, one adult male skeleton was identified as the Tsar, several young adult female skeletons were identified as several of the daughters, and the DNA of several of the other skeletons didn’t match, showing that they were unrelated, family servants. The skeletons of Alexei and one of the four daughters were not with the rest, and are still unaccounted for. After the bones were studied and identified, a few years ago, the remains of the last Tsar of Russia and his family were given a proper funeral and burial.In 1919, a young woman jumped off a bridge in Berlin, Germany and was rescued and hospitalized. While in the hospital, on one occasion she showed a magazine article with a photo of the Russian royal family to a nurse, pointing out to the nurse how much she thought she looked like Anastasia. After that, she claimed to be Anastasia and claimed to have escaped and survived. She later moved to the U. S. and went by the name of Anna Anderson. The rest of her life, she stuck to her story that she was Anastasia, but people were dubious and tried everything they could think of (including things like comparing pictures of ear lobes) to figure out whether she was Anastasia, or not. When she died and was cremated in 1984, no one still knew if she was really Anastasia or not. At some point before her death, she had had surgery, and the hospital had kept the removed tissue preserved in formaldehyde. Again in the 1990s, with the advent of modern DNA technology, scientists were also able to test DNA samples from her preserved tissue and compare those to the other DNA samples, with the result that there were no similarities – she was not related.Another possible use for DNA technology has been suggested. The big question in all of this is, “From where did Victoria get the hemophilia allele?” Neither her mother, Victoria, nor her father, King Edward showed any signs of having that allele. The “standard” explanation which, for many years, has been offered to freshman biology students is that there was a chance, random mutation in that allele on one of Queen Victoria’s X chromosomes. More recently, however, I have heard suggestions that, at that time, if the royal couple was having trouble conceiving a child, it would not have been out of the question to quietly, unobtrusively “loan” the Queen out. People have raised the suggestion that maybe King Edward is not Victoria’s biological father. It has been suggested that perhaps there was not a chance mutation in one of Queen Victoria’s X chromosomes, but that, perhaps, that was inherited from another man. Since the bodies of deceased members of the royal family are in crypts in Westminster Abbey, it would be fairly easy to lift the lids on a couple of crypts to get DNA samples for comparison, but needless to say, the British royal family probably isn’t very enthused about that idea.

Warm up First 3 correct answers = bonus

You are a genetic counselor and couple wanting to start a family comes to you for information

Charles was married once before, and he and his first wife had a child with cystic fibrosis. The brother of his current wife, Elaine, died of cystic fibrosis.

Neither Charles or Elaine have CF.

What is the probability of Charles and Elaine having a baby with CF?

Higher Genetics Pleiotropy – one gene effects many traits

Albinism – 1 mutation in 1 gene affects skin color, eye color, hair color, and eyesight

In mice – coat color affects how they react to light

Epistasis – one gene effects the expression of another bb – brown coat color Bb, BB – black coat color C gene – dominant causes color to be deposited in coat so if no

C gene then white coat color (in case of lab retrievers – yellow)

Polygenic – one trait determined by many genes – continuous pattern

Multifactorial – may be multiple genes and the environment

Linkage

Linkage Mapping – determining where genes are on a chromosome relative to other genes

If 2 genes are on the same chromosome, they will remain together in the gamete – if they don’t stay together it is due to crossing over

The closer two genes are on the same chromosome - the more likely they will stay together and not separate due to crossing over

If you calculate % of the time crossing over occurs and separates the genes, you can tell relatively how far apart they are on the chromosome. (low % close, high % far)

Distance isn’t a real # - it’s just relative – called a map unit or Centimorgan.

Example of Linkage Mapping

If no crossing over – Blonde Hair and Blue Eyed genes will always end up in the gamete together or Brown Hair and Brown Eyes.

If crossing over occurs you can get Blonde Hair and Brown eyes in the same gamete etc.

However, the gamete from this parent will combine with another parent so how do you calculate the % of time crossing over happens?

Blonde hair

Blue Eyes Brown Eyes

Brown Hair

Linkage Mapping continued

Take one parent that is heterozygous for both genes that you want to map and cross them with another parent that is homozygous recessive – any offspring that aren’t like either parent are due to crossing over

Take the # of offspring due to crossing over/# of total offspring = % crossing over = relative distance those gene are from each other

Example:Brown Hair – HBlonde Hair – hBrown Eyes – EBlue Eyes – e

HhEe x hheeAll offspring will be: HhEe and hhee so will look like parents (blonde hair and blue eyes tog. And browns together)

If crossing over:Hhee and hhEe

Problem Practice;Offspring: HhEe – 400 hhee – 400Hhee – 100 hhEe – 100 How many map units are the genes H and E apart?

Linkage Mapping Problem

Problem – if they are really far apart, it may be >50% and cannot be distinguished from being on separate chromosomes

Example of Calculating % Recombination and map

unitsBbTt x bbtt

BT

Bt

bT

bt

X bt =

BbTt

Bbtt

bbTt

bbtt

If the genes are on separate chromosomes:

If on the same chromosome:

BT

btX bt =

BbTt

bbttBut got:965 BbTt – 5944 bbtt – 5206 Bbtt – 1 (these 2 due to185 bbTt – 1 crossing over)

(just like parents)391/2300 = 17% recomb.

17 map units

Practice Linkage Mapping TA = 12 % recombination AS = 5 % recombination TS = 18 % recombination

Pick smallest distance and lay them out

A ------ S

Is T closer to A or S?

T is closer to A so it goes to the left of A

T ------- A ------ S

--------------------

5%

12% 5%

18%

Practice Problems - # 4, 5, 9 Chapter 154. A Wild type fruit fly (heterozygous for gray body and normal wings) is mated with a black fly with vestigial wings.

Offspring:

Wild type 778

Black vestigial 785

Black normal 158

Gray vestigial 162

What is the recombination frequency between these genes for body color and wing size?

Answer: 320/1883 = 17% = 17 map units

5. A wild-type fly (heterozygous for gray body and red eyes) is mated with a black fruit fly with purple eyes.

The offspring:

721 wt

751 black-purple

49 gray-purple

45 black-red

What is the recombination frequency?

What would you mate if you wanted to determin the sequence of body-color, wing-size, and eye color?

Answer: 94/1566=6%Mate heterozygous wing size and eye color (gray,red) and homo rec for wing and eye (vest,purple)

Mapping Problem - #9

Determine the sequence of genes along the chromosome based on the following recombination frequencies.

A-B = 8 map units A-C = 28 A-D = 25 B-C = 20 B-D = 33

Answer: start with smallest distance and work your way out:

D ----25---- A --8-- B ---20---C

Chromosomal Inheritance Aneuploidy – abnormal

chromosome # (ex. Trisomy) Polyploidy – 3n, 4n (non-

disjunction of all chromosomes) More normal than aneuploid –

some plants live fine but can only reproduce with other polyploid plants

2n egg and 1n sperm = 3n

Or Zygote replicates DNA but doesn’t

divide = 4n

Sex Chromosomes and Chromosomal Inheritance

Non-disjuction of sex chromosomes

XXY – Klinefelter’s (small testes, sterile, breasts)

XYY – taller, more aggressive?? Males

XXX – normal female

XO – Turner’s Syndrome (no secondary sex characteristics, sterile, short)

Normal Sex Linked Stuff X-Inactivation – only in females

One x is randomly condensed and inactivated in each cell forming a Barr Body

Methylation causes the condensation and turning off of the genes on the X

Get a mixture of expression in different cells Why does it happen? Need just one active

copy once born (males only have one so if needed both then all males would be abnormal for those traits)

Imprinting – the exact same alleles are expressed as different traits when inherited from the mother vs. father (sperm vs. egg) A female person is a mix of both maternal

and paternal chromosomes but get recoded when form egg – so all imprinted genes in the egg have the maternal coding even if the mother got it from her father

Imprinting Continued The coding is based on methylation

pattern Many times the methylation turns off the

reading of a gene so only the other parent’s allele gets read in the offspring

Example: Deletion of a gene from chromosome 15 If inherited from the father: Prader-Willi (retardation, short, obese, small

hands and feet, insatiable appetite)

If inherited from the mother: Angelman’s (uncontrollable laughter, jerky

motions, loss of coordination)

X-Chromosome Related Stuff Continued

Fragile X – piece of X is hanging on by a thread of DNA

Normally have 50 CGG repeats at end of X

Fragile X – 200 CGG repeats – most common cause of mental retardation

CGG repeats increase over time in the egg making it worse

Much worse also when inherited from the egg (methylated)

More Sex Chromosome Stuff Huntington’s – CAG triplet repeat Elongation more likely to happen if

inherited from the father Note:- mitochondrial DNA is only

inherited from the mother

DiseasesDiseases Specific to Groups Cystic Fibrosis – caucasians (lifespan

27) 1/25 carriers, 1/2500 have it Messed up Cl- channel protein Thicker, stickier mucous Increased infections

Tay Sachs – Ashkenazi Jews Siezures, blindness, loss of coordination,

mental retardation Sickle Cell – African decent 1/10 carrier

Abnormal hemoglobin, resistance to malaria

In-breeding – more likely to have the same recessive genes

Dominant DiseasesDominant Diseases Achondroplasia – dwarfism 1/10,000

Homozygous is lethal Must be a dwarf to have a dwarf offspring Two dwarfs can have a normal child

Huntington’s – nervous degeneration

X-LinkedX-LinkedHemophilia, Color-Blindness

MultifactorialMultifactorial – Heart diseaseDiabetesCancerMental illness