Lecture 10 - 2020 - Pre PDF

2/26/20
Ls1b lecture 10
Non-Mendelian Inheritance
Professor Hopi Hoekstra Thursday February 27, 2020
Mendel published in 1866, but it went unnoticed until the turn of the century.
1
2/26/20
Cuenot’s Odd Yellow Mice
At the start of the 20th century, a number of biologists set out to verify Mendel’s conclusions.
Lucien Cuenot
Cuenot observed Mendelian inheritance of coat colors in mice – first to extend

Mendelian principles to animals – with the exception of the “odd yellow mice.”4
2
2/26/20
Cuenot’s observations: Mendelian pattern
Grey x White mouse:

Either got all grey mice
(GG x gg = Gg)
Or, 1:1 grey to white
(Gg x gg = Gg or gg)
Grey F1 x Grey F1 mouse:

X
3:1 grey to white offspring
F1 F1 (Gg x Gg = 1 GG, 2 Gg, 1 gg)
In most crosses, Cuenot observed Mendelian ratios of coat colors in mice.

5
Cuenot’s observations: non-Mendelian pattern
Yellow x non-yellow mouse:
Always got some non-yellow
Yellow (F1) x Yellow (F1)

mouse:
X
On average, 2:1 ratio of
F1 F1 yellow to non-yellow
But in some crosses, Cuenot observed deviations from Mendelian ratios…..

6
3
2/26/20
Lethal alleles
William Ernest Castle
Recessive lethals will cause deviations from ‘expected’ Mendelian ratios.

7
Molecular details underlying lethal yellow
Raly locus Agouti locus

RNA-binding protein pigmentation gene
Yellow allele (Y) has a 170kb deletion
Raly promoter drives Agouti expression = dominant yellow pigmentation

Deletion of Raly exon = recessive lethality
Lesson: Dominance depends on the phenotype being considered

(e.g., Y allele is dominant for coat color, but recessive for lethality). 8
4
2/26/20
Note: The lack of adherence to Mendel’s rules does not mean

Mendel was wrong; rather, Mendel’s principles are not, alone,
sufficient to explain the inheritance of all genetic traits.
Lecture 10: Non-Mendelian Inheritance
Story: Cuenot’s Odd Mice
Effects of single loci on inheritance patterns

Dominance
Penetrance and expressivity
Multiple alleles
Effect of multiple loci on inheritance patterns
epistasis
Influence of sex on inheritance
Sex-linked traits (both X- and Y-linked) Uh oh.
Sex-limited traits
Sex-influenced traits
Cytoplasmic inheritance
Maternal effect genes
Organelles (mtDNA, chloroplasts)
Environmental effects
Temperature-sensitive alleles
Maternal environment
Genetic imprinting (sex-specific silencing of genes)
Sexual conflict theory in mice
Imprinting and disease
10
5
2/26/20
Incomplete dominance
Complete dominance Incomplete dominance
Flowers heterozygous for ‘red’

and ‘no’ pigment alleles have
intermediate phenotype.
Note: Heterozygous phenotype need not be perfectly intermediate (just different from homozygous).
Heterozygote phenotype is intermediate between homozygotes.

11
Co-dominance
This heterozygous flower has both red Human blood groups: each allele expresses a
and white patches on its petals. different cell surface antigen (or none at all).
(Note: flower is not an intermediate pink) The A and B alleles are considered co-dominant.
Heterozygote simultaneously expresses phenotypes of both homozygotes.

12
6
2/26/20
Summary of dominance relationships
13
Incomplete penetrance
Penetrance = % of individuals with a particular genotype that express the expected phenotype.
Polydactyly in cats is
Wildtype cats have 18
inherited as an
toes: 5 toes on each
autosomal dominant
front paw and 4 on each
trait controlled by the
hind paw; polydactyl
Pd gene with
cats have extra toes.
incomplete penetrance.
Some cats with the Pd mutation have extra digits but other cats don’t.
Genotype doesn’t always produce the expected phenotype. Instead, the genotype
has a certain probability of expressing the phenotype, referred to as the penetrance.
14
7
2/26/20
Variable expressivity
Some cats with the Pd mutation have 1 extra digit others have 2 or even 3 extras.
When an individual has a trait, it can be expressed to different degrees (e.g. an

affected individual may have a mild or severe phenotype).
15
Multiple alleles at a single locus
Note: The
genotype of any
diploid individual
can have only 2
CC, CCch, CCh, Cc CchCch, Cchc ChCh, ChCch, Chc cc
alleles, however
>2 alleles may
occur in a
population of
individuals.
Multiple alleles provide a greater number of possible genotypes/phenotypes than just 2 alleles.
16
8
2/26/20
Multiple traits and multiple genes
Respiratory, digestive, reproductive system

all effected by a single gene mutation
Pleiotropy: One gene has an effect on many traits.
Almost 400 genes known to affect pigmentation
Polygenic: Many genes contribute to the expression of one trait. 17
Epistasis
Spotting gene: white-spot or black-spot allele (Gene 1)
Background gene: white fur or black fur allele (Gene 2)
Whether or not the spotting genotype is visible depends on the background color/genotype.
The effect of one allele can depend on the genotype at another locus.
18
9
2/26/20
Epistasis: an example
Dihybrid cross
Under Mendelian expectations
(in a dihybrid cross), we would
expect a 9:3:3:1 ratio of
phenotypes. This assumes the
two loci act independently.
BC Bc bC bc
B- C-
BC BBCC BBCc BbCC BbCc
B- cc
Bc BBCc BBcc BbCc Bbcc
bb C- bC BbCC BbCc bbCC bbCc
bb cc bc BbCc Bbcc bbCc bbcc
19
Here we do not see the canonical
9:3:3:1 outcome because Dihybrid cross
homozygosity of the recessive c
allele at one locus prevents the
expression of the B/b genotype
(ie, any pigment being produced).
We therefore see a 9:4:3 ratio.
BC Bc bC bc
Two loci involved in pigmentation:
Is pigment produced?
C - = Yes Bc BBCc BBcc BbCc Bbcc
cc = No
If pigment produced, then: bC BbCC BbCc bbCC bbCc
B - = grey
bb = brown bc BbCc Bbcc bbCc bbcc
20
10
2/26/20
Dihybrid cross
What happens to the phenotypic

ratio, if the dominant C allele
prevents pigmentation production?
BC Bc bC bc
C - = No Bc BBCc BBcc BbCc Bbcc
cc = Yes
B - = grey
21
Dihybrid cross
BC Bc bC bc
C - = No Bc BBCc BBcc BbCc Bbcc
cc = Yes
B - = grey
22
11
2/26/20
Why Mendel was smart (or lucky).
He avoided:
• Incomplete dominance
• Co-dominance
• Incomplete penetrance
• Variable expressivity
• Multiple alleles at a locus
• Pleiotropy
• Polygenic traits
• Epistasis
23

Dominance
Multiple alleles
epistasis
Sex-limited traits
24
12
2/26/20
Sex-linked traits
Trait of interest: white eyes

recessive; X-linked
A sex-linked trait is controlled by a gene on one of the sex chromosomes.

25
Sex-linked traits
What is the
phenotypic ratio of
the reciprocal cross?
In one cross, a male expressing the
trait of interest will be crossed with
a female not expressing the trait. In
the other, a female expressing the
trait of interest will be crossed with
a male not expressing the trait.
Trait of interest: white eyes

recessive; X-linked
A sex-linked trait is controlled by a gene on one of the sex chromosomes.

26
13
2/26/20
Breakout 1
What is the
phenotypic ratio of
the reciprocal cross?
A. All red-eyed
B. All white-eyed
C. Half red and half white (1:1)
D. One third red, two thirds white (1:2)
E. One third white, two thirds red (2:1)
F. One quarter red, three quarters white (1:3)
G. One quarter white, three quarters red (3:1)
27
Breakout 1
28
14
2/26/20
Breakout 1
29
Problem
Last lecture we discussed how few genes are on the mammalian Y
chromosome (2% of the DNA in the genome, and only ~75 genes).
How can males have so many unique traits not found in females
(and vice versa)?
30
15
2/26/20
Sex – influenced characteristic

males females
Male Female
Genotype Phenotype Phenotype
B+ B+ beardless beardless
BB + b bearded beardless
Bb Bb bearded bearded
Autosomal genes can be expressed differently in males and females.

31
Sex – limited characteristic
Cock-feathered male hen-feathered female hen-feather male
Male Female
Genotype Phenotype Phenotype
HH hen feathering hen feathering
Hh hen feathering hen feathering
hh cock feathering hen feathering
Autosomal genes can be expressed ONLY in one sex.

32
16
2/26/20
Breakout 2
In humans, the hypothetical gene BLD causes balding. For both

males and females, individuals homozygous for the BLD allele
are not bald and individuals homozygous for the wild-type BLD+
allele are bald. Interestingly, heterozygous males are bald and
heterozygous females are not bald. This trait is likely ________.
A. sex-linked
B. sex-limited
C. sex-influenced
D. autosomal dominant
E. sex-limited or sex-influenced
33
Breakout 2
34
17
2/26/20

Dominance
Multiple alleles
epistasis
Sex-limited traits
35
Misconception
Sperm and egg are created equal
36
18
2/26/20
Cytoplasmic (or “extranuclear”) inheritance
(1) Maternal effects:

genes, mRNAS and
transcription factors
(2) Organelles:
Mitochondria and
Chloroplast DNA
sperm egg
Factors in the egg cytoplasm can influence or be passed on to offspring.
37
Maternal effect gene
An example of a maternal effect gene: Bicoid (BCD)
The maternal effect gene Bicoid codes for mRNA that localizes to the anterior tip of the egg.
Upon fertilization, the RNA is translated to protein, which sets up the anterior-posterior axis.
mRNA or protein already in the egg/zygote that is thus passed from the mother to offspring.
38
19
2/26/20
Coiling in snails
39
Inheritance pattern of a maternal effect
Phenotype of the offspring is determined by the genotype of the mother.

(Genes are inherited from both parents, and male genotype contributes to his
daughter’s genotype which affects phenotype of F2 generation.) 40
20
2/26/20
Problem:
Not all genes are encoded in the nuclear chromosomes
41
Organellar inheritance
Animals (and Plants) Plants
Mitochondrial DNA (mtDNA) Chloroplast DNA (cpDNA)

~30 genes ~125 genes
16kb 120kb
~2000 per cell 1-100 per cell
Autosomal genes are inherited from both parents,

cytoplasmic genes from one gamete, usually the egg.
42
21
2/26/20
Inheritance pattern of organellar genes
Characteristics of cytoplasmically inherited traits:
• Present in both males and females
• Usually inherited from one parent

(usually the mother)
• Reciprocal crosses can give different results
• Can exhibit extensive phenotypic variation

(even within a family)
Cytoplasmic genes have unique

patterns of inheritance.
43
Organellar inheritance: example from mitochondria
Mitochondrial disease:
Leber hereditary optic
neuropathy (LHON)
Healthy vision Affected vision
A few rare human diseases are caused by mutations in mtDNA (and have cytoplasmic inheritance
patterns, ie. inherited from mother to sons and daughters, variability in severity within families).
44
22
2/26/20
Mitochondria replacement therapy: transgenics using a mtDNA donor
Sept 2016
An option when a
woman has
genetically flawed
mitochondria:
45

Dominance
Multiple alleles
epistasis
Sex-limited traits
46
23
2/26/20
Environmental Effects: abiotic influence
Enzyme necessary for the production of dark pigment is inactivated at higher temperatures.
The external environment can influence an individual’s phenotype,

independent of its genotype. 47
Environmental Effects: biotic influence
The maternal environment (or condition of the mother) can influence her
offspring’s phenotype, independent of the offspring's genotype. 48
24
2/26/20
A biologist’s ode to his mother
Maternal environment (nutrients), mtDNA, cytoplasmic mRNA and TFs, X chromosome, etc.
49

Dominance
Multiple alleles
epistasis
Sex-limited traits
50
25
2/26/20
Misconception
We assume the expression of a gene doesn’t

depend on the parental origin (i.e., if it is
inherited from the mother vs. father).
51
Genomic Imprinting
insulin-like growth factor 2
Note that this parent-of-origin-based

silencing is gene-specific, not
chromosome-region-specific. Igf2,
similarly imprinted in both mouse and
human, is on mouse chromosome 7
but human chromosome 11.
Genomic imprinting = an allele is differentially expressed, depending on

whether it is inherited from the male or female parent. 52
26
2/26/20
The Sexual Conflict Hypothesis
In promiscuous systems:
Males: mate with a given female once, thus

favor provisioning his offspring with
nutrients (higher survival/success rate) at
mother’s expense.
= favors large offspring
Females: may mate with many males, thus

favor spreading her resources out across
litters (and doesn’t put ‘all her eggs in one
basket’).
= favors smaller offspring
Consistent with observation that many imprinted genes are involved in growth/metabolism.
Conflict of interest between parents sets up a battle between the sexes.

53
The Sexual Conflict Hypothesis: empirical evidence
mother father embryo adult
X =
P. maniculatus P. polionotus
promiscuous monogamous
X =
P. polionotus P. maniculatus
monogamous promiscuous
Reciprocal crosses produce different hybrid phenotypes, consistent with sexual conflict.
54
27
2/26/20
55
5
6
28
2/26/20
The Sexual Conflict Hypothesis: more empirical evidence
X X
Father Mother Father Mother

Multiple mates Single mates
Liger (large) Tigon (small)
Reciprocal F1s
If imprinting differs in 2 species, effects can be observed in the reciprocal hybrid offspring.
57
Genomic imprinting and disease
Paternal copy is expressed in most cells, while the maternal copy is silenced,
But, in some regions of the brain, the maternal copy is expressed.
Prader-Willi syndrome Angelman syndrome

Paternal deletion in chrm15 Maternal deletion in chrm15
Genomic imprinting has been implicated in several human disorders:

different disease phenotypes depending on if maternal or paternal allele is mutated.58
29
2/26/20
Breakout 3
I may see phenotypic differences in offspring from

a reciprocal cross, if the underlying genes are:
A. Cytoplasmically inherited
B. Sex-linked
C. Subject to imprinting
D. All of the above.
E. None of the above.
59
Breakout 3
60
30
2/26/20
Problem
The maternal allele in one generation can be

the paternal allele in the next generation
(and vice versa).
61
• My son Henry received a copy of

chromosome 8 from me.
• I have 2 chromosome 8s, one

inherited from my father and
one from my mother.
• 50% chance Henry received the

chromosome 8 that I inherited
from my father.
• If so, that chromosome 8 is the

“paternal” copy in me, but the
“maternal” copy in my son
Henry.
• Thus, every generation, the

maternal v. paternal “marks”
need to be reset.
62
31
2/26/20
Molecular mechanisms underlying imprinting patterns
Maternally
silenced
Paternally
silenced
The “tags” on imprinted genes usually stay put for the life of the
organism, but are reset during egg and sperm formation 63
The extreme: imprinting of entire genomes

based on parent-of-origin
Coccids (scale insects) show transcriptional

silencing of all the paternally contributed
chromosomes in males. Thus, genomic
imprinting and the resultant differential
regulation operate on 50% of the genome.
While most imprinting is gene-specific, some organisms can silence

entire chromosomes or genomes based on their parent-of-origin.
64
32
2/26/20
How does imprinting (and other phenomenon

like X-inactivation) work at the molecular level?
Next lecture: Epigenetics
65
Want to know more?
Posted on the website:
• Read Lecture Notes (and Chapter 5 in Pierce Genetics)

• Read FAQs
• Review Concept Check
• Review Learning Goals
• Do practice problems
• Read the Tutorial
• Mother’s Day song

• National Geographic clip on ligers and tigons
• Module on Non-Mendelian inheritance
• Link to information on William Castle and Harvard
• NYTs article on mitochondrial manipulation technology
66
33

Lecture 10 - 2020 - Pre PDF

Загружено:

Сведения о документе

Исходное описание:

Оригинальное название

Авторское право

Доступные форматы

Поделиться этим документом

Поделиться или встроить документ

Параметры публикации

Этот документ был вам полезен?

Это неприемлемый материал?

Авторское право:

Доступные форматы

Lecture 10 - 2020 - Pre PDF

Загружено:

Авторское право:

Доступные форматы

2/26/20

Professor Hopi Hoekstra Thursday February 27, 2020

Cuenot’s Odd Yellow Mice

Cuenot observed Mendelian inheritance of coat colors in mice – first to extend

Cuenot’s observations: Mendelian pattern

Grey x White mouse:

Grey F1 x Grey F1 mouse:

In most crosses, Cuenot observed Mendelian ratios of coat colors in mice.

Cuenot’s observations: non-Mendelian pattern

Yellow x non-yellow mouse:

Always got some non-yellow

Yellow (F1) x Yellow (F1)

But in some crosses, Cuenot observed deviations from Mendelian ratios…..

William Ernest Castle

Recessive lethals will cause deviations from ‘expected’ Mendelian ratios.

Molecular details underlying lethal yellow

Raly locus Agouti locus

Yellow allele (Y) has a 170kb deletion

Raly promoter drives Agouti expression = dominant yellow pigmentation

Lesson: Dominance depends on the phenotype being considered

Note: The lack of adherence to Mendel’s rules does not mean

Lecture 10: Non-Mendelian Inheritance

Story: Cuenot’s Odd Mice

Effects of single loci on inheritance patterns

Complete dominance Incomplete dominance

Flowers heterozygous for ‘red’

Heterozygote phenotype is intermediate between homozygotes.

Heterozygote simultaneously expresses phenotypes of both homozygotes.

Summary of dominance relationships

When an individual has a trait, it can be expressed to different degrees (e.g. an

Multiple alleles at a single locus

Multiple traits and multiple genes

Respiratory, digestive, reproductive system

Pleiotropy: One gene has an effect on many traits.

Almost 400 genes known to affect pigmentation

Polygenic: Many genes contribute to the expression of one trait. 17

Background gene: white fur or black fur allele (Gene 2)

What happens to the phenotypic

Why Mendel was smart (or lucky).

Lecture 10: Non-Mendelian Inheritance

Story: Cuenot’s Odd Mice

Effects of single loci on inheritance patterns

Trait of interest: white eyes

A sex-linked trait is controlled by a gene on one of the sex chromosomes.

Trait of interest: white eyes

A sex-linked trait is controlled by a gene on one of the sex chromosomes.

Sex – influenced characteristic

Autosomal genes can be expressed differently in males and females.

Sex – limited characteristic

Cock-feathered male hen-feathered female hen-feather male

Autosomal genes can be expressed ONLY in one sex.

In humans, the hypothetical gene BLD causes balding. For both

Lecture 10: Non-Mendelian Inheritance

Story: Cuenot’s Odd Mice

Effects of single loci on inheritance patterns

Sperm and egg are created equal

Cytoplasmic (or “extranuclear”) inheritance

(1) Maternal effects:

Maternal effect gene

An example of a maternal effect gene: Bicoid (BCD)

Inheritance pattern of a maternal effect

Phenotype of the offspring is determined by the genotype of the mother.