Professional Documents
Culture Documents
Httpsestudijas - Rsu.lvpluginfile - Php1654057mod Resourcecontent1MedGen1 RSU 2020 E 3.PDF 6
Httpsestudijas - Rsu.lvpluginfile - Php1654057mod Resourcecontent1MedGen1 RSU 2020 E 3.PDF 6
Edvīns Miklaševičs
10.02.2020.
Medical Genetics
1
Nam ut medici causa morbi inventa
curationem esse inventam putant, sic
nos causa aegritudinis reperta medendi
facultatem reperiemus.
M. TVLLI CICERONIS TVSCVLANARVM DISPVTATIONVM LIBER TERTIVS
2
Content
‹#›
Subject of medical genetics
4
de’ Medici
Leopoldo
(1617 - 1675)
Giuliano (1479 -
Lorenzo (1449 - 1492)
1516)
Genetics
Oxford Dictionaries 8
Genetics vs Molecular biology
Oxford Dictionaries 9
Genetics vs Molecular biology
to generation,
phenotype seg-
regation.
Museum
für Naturkunde
Berlin 10
Genetics - heredity and the variation of
inherited characteristics
Museum
für Naturkunde
Berlin 11
Genetics vs Molecular biology
12
Essentialist vs Nominalist
13
bility emergence followed by disappearance. This pattern is a key point,
blem as we will see when we return to consider the evolutionary impli-
aken Human
cations of themortality curves
genetic theory of infectious diseases. The global in-
ts to fectious burden was caused mostly by primary infections, striking
par-
more
atter
artial
f the
ame
lle’s
nly a
and
arles
s his
ww.
pres- Fig. 1. Human mortality curves. Mortality curves at various periods of hu-
f an man history, from the Paleolithic period (<10,000 BC) to modern times (2000
y be AD). Contemporary data for the 2015,
Casanova United Kingdom
Proc. andSci.
Natl. Acad. Mozambique are avail-
USA, 112, E7118 - E7127.
‹#›
ales- able from the WHO site (www.who.int/topics/global_burden_of_disease). Older
bility emergence followed by disappearance. This pattern is a key point,
blem as we will see when we return to consider the evolutionary impli-
aken Human
cations of themortality curves
genetic theory of infectious diseases. The global in-
ts to fectious burden was caused mostly by primary infections, striking
par-
more
atter
artial
f the
ame Microbiology
lle’s
nly a
and
arles
s his
ww.
pres- Fig. 1. Human mortality curves. Mortality curves at various periods of hu-
f an man history, from the Paleolithic period (<10,000 BC) to modern times (2000
y be AD). Contemporary data for the 2015,
Casanova United Kingdom
Proc. andSci.
Natl. Acad. Mozambique are avail-
USA, 112, E7118 - E7127.
‹#›
ales- able from the WHO site (www.who.int/topics/global_burden_of_disease). Older
Causes of death in the USA, 1900 -
2010.
Cardiovascular diseases
Influenza
Oncological diseases
Tuberculose
17
Continuity of disease across the lifetime
Schizophrenia
Bipolar disoders
Astma
Cardiovascular diseases
Oncological diseases
18
9 Other
Proportional Contribution to Premature
Death Proportional Contribution to Premature Death
Social
p-Ranked
Genetic circumstances
ry in OECD* 15%
predisposition
30%
Environmental
exposure
celand 5%
7 deaths/
live births) Health care
10%
itzerland
4 deaths/
000 births) Behavioral patterns
40%
Schroeder, 2007, N. Engl. J. Med. , 357, 1221 - 1228. ‹#›
Figure 1. Determinants of Health and Their Contribution
bility emergence followed by disappearance. This pattern is a key point,
blem as we will see when we return to consider the evolutionary impli-
aken Human
cations of themortality curves
genetic theory of infectious diseases. The global in-
ts to fectious burden was caused mostly by primary infections, striking
par-
more
atter
artial Genetics
f the
ame
lle’s
nly a
and
arles
s his
ww.
pres- Fig. 1. Human mortality curves. Mortality curves at various periods of hu-
f an man history, from the Paleolithic period (<10,000 BC) to modern times (2000
y be AD). Contemporary data for the 2015,
Casanova United Kingdom
Proc. andSci.
Natl. Acad. Mozambique are avail-
USA, 112, E7118 - E7127.
‹#›
ales- able from the WHO site (www.who.int/topics/global_burden_of_disease). Older
■ Understanding basic cause of disease and creating
new targets for prevention and therapy
■ Newborn screening
■ Identification of risk allele carrier and genetic
consulting
■ Family planning
■ New approaches in medicine
■ pharmacogenetics
■ gene therapy
■ targeted therapy
‹#›
Causes of phenotypical variability
22
Phenotype
Genes 23
The ontogenic pyramid
Astolfi et al.
repositioning
repeats (long
aberrations.
hromosomes
ucleus, as in
the aegis of a
ineages, and
may display
age stage hu-
amatic insur-
tions, admit-
; see also the
in this issue]
rtions of zy-
erging germ
e insurgence
Conversely, a
Fig. (1). The “ontogenic pyramid”.
Astolfi etThe phenotype
al., 2010, (PHE)
Current may be 11, 379 - 386.
Genomics,
nd associated
seen as the result of four variables: the original zygotic genome 24
een environ-
1 cell Cell divisions 1012 - 1013
cells
25
1 cell Cell divisions 1012 - 1013
cells
Retina 55
Intestinal epithelium 600
Germline 216
Folding of
antihelix
Tragus size
Antitragus
size
rs10212419
rs2080401
rs17023457
12.5
rs263156
12.0
11.5
11.0
rs1619249
10.5
rs1960918
10.0
9.5
9.0
8.5
8.0
–Log10 (P)
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Chr1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X XY
Figure 1 | Genome-wide associations of pinna traits. Variation in 10 pinna traits was evaluated in 5,062 individuals. The photographs at the top
indicate the location of the traits examined. At the bottom is shown a composite Manhattan plot for the seven traits showing genome-wide significant
Adhikari et al., 2015, Nat. Commun., 6: 7500.
association with at least one genome region. The rs numbers for the most significantly associated (index) SNP in each region are provided (Table 1).
‹#›
Each of the seven regions on the Manhattan plot is connected with the associated trait on the photos via a line of different colour (composite panels
Darwin’s tubercle Superior crus of
antihelix expression
Folding of
antihelix
Tragus size
Antitragus
size
rs10212419
rs2080401
rs17023457
12.5
rs263156
12.0
EDAR
11.5
11.0
rs1619249
10.5
rs1960918
10.0
9.5
9.0
8.5
8.0
–Log10 (P)
7.5
7.0
6.5
6.0
5.5
5.0
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
0.5
0.0
Chr1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X XY
Figure 1 | Genome-wide associations of pinna traits. Variation in 10 pinna traits was evaluated in 5,062 individuals. The photographs at the top
indicate the location of the traits examined. At the bottom is shown a composite Manhattan plot for the seven traits showing genome-wide significant
Adhikari et al., 2015, Nat. Commun., 6: 7500.
association with at least one genome region. The rs numbers for the most significantly associated (index) SNP in each region are provided (Table 1).
‹#›
Each of the seven regions on the Manhattan plot is connected with the associated trait on the photos via a line of different colour (composite panels
EDAR pathway
EDA-A1/NF-jB €gren’s syndrome
signalling in Sjo
n
of
ck
d
of ■ EDAR pathway deter-
ly
v-
mines development of
d ectodermal appenda-
].
d ges (e.g. hair folicules,
lt teeth, glands), their
d
al localization, size and
n shape.
c-
l-
ne
he
n
ne
as Fig. 7. A simplified overview of the ectodysplasin/EDA-receptor/ Sisto et al., 2016, British Soc. Immunol.,
nuclear factor kappa B (EDA/EDAR/NF-jB) pathway. Trimeric ‹#›
es
receptor EDAR is activated by trimeric ligand EDA leading to the Clin. Experimen. Immunol.,184, 183–196.
Effect of allelic variant of the Edar gene
on the shape of ears
c
wt/wt Val370Ala/Val370Ala
ncbi.nml.nih.gov/clinvar‹#›
Allelic variants of the EDAR gene
NATURE COMMUNICATIONS | DOI: 10.1038/ncomms8500
b c
d e
100 ncbi.nml.nih.gov/clinvar
0.25
‹#›
Allelic variants of the EDAR gene
EDAR mutations in HED
AH van der Hout et al
676
van der Hout et al., 2008, Europ. J. Hum. Genet., 16, 673 - 679.
‹#›
Allelic variants of the EDAR gene
BMC Medical Genetics 2006, 7:80 http://www.biomedcentral.com/1471-2350/7/80
! pathogenic
! likely pathogenic
! uncertain significance
! likely benign
! benign
ACMG Guidelines 38
DIGNUM MEMORIA
‹#›
DIGNUM MEMORIA
‹#›
Causes of diversity of allelic variants
41
RICHARD ET AL. MICROBIOL. MOL. BIOL.
G. 1. Repeated DNA sequences in eukaryotic genomes and mechanisms of evolution. The two main categories of repeated elements (tan
ats and dispersed repeats) are shown, along with subcategories, as described in the text. Blue arrows point to molecular mechanisms tha
ved in propagation and evolution of repeated sequences. REP, replication slippage; GCO, gene conversion; WGD, whole-genome du
SEG, segmental duplications; RTR, reverse transcription; TRA, transposition.
Richard et al., 2008, Microbiol. Molecular Biol. Rev., 72, 686 – 727. 42
! Alterations in number of chromosomes
! Remodeling of chromosomes
43
Mutations
44
Causes of mutations
! Endogenous
! Environmental
45
Causes of mutations
! Endogenous
» DNA replication errors
» reactive oxygen compounds arising as byproducts from
oxidative respiration
! Environmental
46
DNA replication
47
The ontogenic pyramid
Astolfi et al.
repositioning
repeats (long
aberrations.
hromosomes
ucleus, as in
the aegis of a
ineages, and
may display
age stage hu-
amatic insur-
tions, admit-
; see also the
in this issue]
rtions of zy-
erging germ
e insurgence
Conversely, a
Fig. (1). The “ontogenic pyramid”.
Astolfi etThe phenotype
al., 2010, (PHE)
Current may be 11, 379 - 386.
Genomics,
nd associated
seen as the result of four variables: the original zygotic genome 48
een environ-
Causes of mutations
! Endogenous
! Environmental
» ultraviolet light
» ionizing radiation
» chemicals
- tobacco products
- food contaminants
- heterocyclic amines in overcooked meals
49
Relative risk of melanoma associated with
Schulman and Fisher Page 11
Figure 2. Schulman & Fisher 2009, Curr. Opin Oncol., 21, 144 –149.
Relative risk of melanoma associated with early first exposure to indoor tanning: estimates 50
(http://cdn2.artboom.info/wp-content/uploads/2011/11/Fernando-Vicente-11.jpg)
Fernando Vicente51
2FLARES (http://filament.io/flare?
Most common specific causes of death: 12-year
relative risk, current versus never-smoker
Number of deaths RR (95% CI)
samp
Current Never
base
smoker smoker thos
Chronic lung disease (J40–44) 1789 121 35·3 (29·2–42·5) neve
Cancer of lung (C34) 5633 698 21·4 (19·7–23·2) diffe
Aortic aneurysm (I71) 330 164 6·32 (5·17–7·71) body
Intestinal ischaemia (K55) 183 91 5·58 (4·27–7·29) Th
Cancer of mouth, pharynx, larynx, 204 91 4·83 (3·72–6·29) resu
nasal cavity, or sinuses (C00–14,30–32) smok
Coronary heart disease (I21–25) 2726 1732 4·47 (4·19–4·77) (424 2
Cirrhosis or alcoholic liver (K70,74) 478 256 3·35 (2·84–3·94) answ
Cancer of bladder (C67) 178 156 3·29 (2·61–4·15) of th
Cancer of oesophagus (C15) 450 397 3·10 (2·68–3·58) of n
Pneumonia (J12–18) 494 408 3·09 (2·68–3·56)
ex-sm
Cerebrovascular disease (I60–69) 1528 1458 3·06 (2·83–3·31)
at b
Cancer of pancreas (C25) 809 1082 2·30 (2·08–2·53)
(26 4
Cancer of kidney (C64) 246 360 2·10 (1·77–2·50)
(37 2
Cancer of stomach (C16) 247 329 2·00 (1·67–2·39)
comm
Diabetes (E10–14) 122 192 1·81 (1·43–2·31)
still
External causes* (V01–Y98) 487 677 1·76 (1·56–2·00)
Pirie et al., 2013, Lancet, 381, 133 – 141.havin
Pulmonary fibrosis (J84·1) 88 162 1·53 (1·16–2·01) 52
smok
espite female smokers.
ks by Because the absolute hazards of prolonged smoking
opped All-cause
are substantial,mortality: Illustration
so too are the of the
absolute benefi ts ofeffects of a 3-fold
rtality difference
cessation. Even in annual
cessation at death
about 50rates
years on
of agemortality from age
35 years
avoids at leastto age 80of years
two-thirds the continuing smoker’s
n non-
r than Smokers 53%
50 Non-smokers
cause
ate of
Hence, 40
died,
oking
nes in 30
Mortality (%)
with 24%
g less 11 years
22%
ghout 20
rettes,
n half 10% 11 years
10
ed by 9%
s.
4%
s and 0
35 40 45 50 55 60 65 70 75 80
was of
Age (years)
years).
moker Figure 5: All-cause mortality: Illustration of the effects of a 3-fold difference in annual death rates on
so the mortality from age 35 years to age 80 years Pirie et al., 2013, Lancet, 381, 133 – 141.
53
an be This hypothetical example takes age-specific death rates in non-smokers to be two-thirds of the UK 2010 female
y, or
give Continuing cigarette smoker
0.23 24 Cigarette smoker until age 50
ALY Cigarette smoker until age 30
ety’s Lifelong non-smoker
35
who
lung cancer by age 75 (%)
Cumulative risk of death from
UK mean 21 Bq/m3
30
25
20
15
sible
rom 10
d the 5
that
0
nted 0 200 400 600 800
with Long term average radon (Bq/m3)
en in
Fig 1 | Cumulative risk of deathGray
fromet al.,lung cancer
2009, BMJ, bydoi:10.1136
338:a3110 age 75bmj.a3110 54
DSBs plays a major role in checkpoint phosphorylation following DNA dam- lon
activation, the relationship could be dif- age to form discrete foci ( H2AX foci) tiv
ferent. Moreover, the larger genome of was exploited to monitor unrepaired lon
Ionizing radiation
mammalian cells may confer a different
sensitivity threshold.
DSBs at the time of checkpoint release,
and mitotic entry and the formation of
the
tha
ref
dem
Transatlantic flight Moon walk Mars travel the
Fu
Background def
level Thoracic X-ray Diagnostic CT Tumour therapy che
DS
is r
bel
tak
10 µSv 100 µSv 1 mSv 10 mSv 100 mSv 1 Sv 10 Sv 100 Sv
Radiation dose
for
He
fro
cel
Cancer risk (estimated) 0.01 % 0.1 % 1 10 % rep
no data available data available
tiv
Figure 3 | Encounters with IR exposures and risk estimation. The chart displays
Nature the ionizing
Reviews | Cancer
che
radiation (IR) doses encountered from a range of situations, starting from the daily background radia-
tion level of ~5 Sievert ( Sv) to doses of almost 100 Sv delivered cumulatively during radiotherapy. des
Sv is the unit of the equivalent or effective dose, and is equal to the dose in Gy multiplied by a weight- ing
Löbrich & Jeggo, 2007, Nat. Rev. Cancer, 7, 861-869.55
ing factor for different radiation qualities and different tissues. For a whole-body exposure with X- or no
Type of Cancer Observed Expected SIR (95% CI)
1.67 (0.86-2.92)
44.32 1.35 (1.03-1.74)
attendants
Lung and bronchus 3 7.90 0.37 (0.07-1.12)
Compared to women of all races, AFA members exhibited similarly elevated breast
cancer incidence (Table 5), as well as significantly more melanoma.
Table 6. Proportional Incidence Ratios of invasive cancers among female flight attendants, ages
20-64, 1988-1995 all races cancer reference proportions.
Type of Cancer Observed Expected SIR (95% CI)
56
Fernando Vicente 11 - ARTBoom 21.01.15 20:17
Astolfi et al.
2FLARES (http://filament.io/flare?
CHERNOBYL NUCLEAR POWER PLANT Fernando Vicente 11 See the full size image (
RUSSIA
61
Somatic mutations
T T TCTTGCAGCGTGTCTTAAAAATTCAAAAAA
T T TGTTGCAGCGTGTCATAAAAATTCAAAAAA
T T TGTGGCAGCGTGTCTTAAAAATTCAAAGAA
T T TGTTGCAGCGTGTCTTAAAAATTCTAAAAA
T T TGTTGCACCGTGTCTTAAAAATTCAAAAAA
C T TGTTGCAGCGTGTCTTAAAAATTCAAAAAA
T T TGTTGCAGCGTATCTTAAAAATTCAAAAAA
T T TGTTGCAGCGTGTCTTAA-AATTCAAAAAA
T T TGTTCCAGCGTGTCTTAAAAATTCAAAAAA
T T TGTTGCAGCGTGTCTTAAAAATTCAAAAAG
T T TGTTGCAGCGTGTCTAAAAAATTCAAAAAA
T T TGATGCAGCGTGTCTTAAAAATTCAAAAAA
T T TGTTGCAGCGTGTCTTAAAAATGCAAAAAA
T T TGTTGCAGCCTGTCTTAAAAATTCAAAAAA
62
St. Jerome
64
Somatic mutations
65
Tissue-specific frequencies of mutations
as a function of age in mouse lines
Fibroblast 1.34
Lymphocytes 1.47
Average 1.02
Lynch 2010, Proc. Natl. Acad. Sci. USA, 107, 961 - 968.
68
! With a diploid genome size of 6 × 109 sites and ~1013
cells per soma, the body of a middle-aged human
might then contain >1016 mutations (not including
insertions, deletions, or other larger scale mutations).
70
The ontogenic pyramid
Astolfi et al.
repositioning
repeats (long
aberrations.
hromosomes
ucleus, as in
the aegis of a
ineages, and
may display
age stage hu-
amatic insur-
tions, admit-
; see also the
in this issue]
rtions of zy-
erging germ
e insurgence
Conversely, a
Fig. (1). The “ontogenic pyramid”.
Astolfi etThe phenotype
al., 2010, (PHE)
Current may be 11, 379 - 386.
Genomics,
nd associated
seen as the result of four variables: the original zygotic genome 71
een environ-
Somatic mosaicism
72
73
Somatic mosaicism
74
Somatic mosaicism
75
Clinical,L Ehistological
TTERS and molecular
analysesa of nevus sebaceous Figure 1 Clinical, histological and
(a) Nevus sebaceous presenting a
plaque on the scalp. (b) Histopath
(from subject no. 52) comprise ep
sebaceous and apocrine glands, a
is present at the left and right ma
(c) Sanger sequencing chromatog
(left) and nevus sebaceous (right)
arrowhead indicates a c.37G>C p
WT
MUT
WT
ITARY TYROSINAEMIA WT
Blood MUT
MUT
osomal-recessive disorder
ine metabolism that is WT Normal
deficiency of the enzyme skin
MUT
lacetoacetate hydrolase.
order typically causes
d renal problems early in WT Abnormal
is associated with MUT skin
ogical deterioration and
ma. Figure 2 | Diagnostic methods for somatic and germ-line mosaicism. a | Hypothetical pedigree of S
NEUROFIBROMATOSIS TYPE I and (below) molecular
Youssoufian & analysis
Pyeritz showing somatic
2002, Nat. Rev.mosaicism.
Genet., 3,The
748three-generat
- 758.
78
ENEIC ORGAN occurrence of a sporadic mutation (shown in red) in a second-generation male (represented as squares) m
es derived mosaicism for activating HRAS and KRAS mutations involving the
g from 12% skin, skeletal, ocular and central nervous systems is the underlying
nocytes. InSchimmelpenning - Feuerstein - Mims
genetic cause of Schimmelpenning syndrome.
ndividuals
n 13. These
syndrome
mutation in a b C T G G/A T G G C
cells of the
ng genetic Nevus
sebaceous
ary tumors
pilliferum,
he associ- C T G G T G G C
xclusively;
Nonlesional
skin
elpenning
xtensive C T G G T G G C
ell as
otograph
omatograms Blood
found in
ytes showed
OMIM #163200
Groesser et al., 2012, Nat. Genet., 44, 783 - 788.
79
Schimmelpenning - Feuerstein - Mims
syndrome
OMIM #163200
Amato et al., 2010, AJNR Am. J. Neuroradiol., 31, E47–E4880
The timing of post-zygotic mutation influences
the distribution of mutant cells in the individual
Campbell et al. P
81
Inflammatory nevus affecting the left side of the
Campbell et al.
body of a 1-month-old individual with CHILD
syndrome
Author Manuscript
82
A
Mosaic overgrowth with fibroadipose hyperplasia is
caused by somatic activating mutations in PIK3CA
overgrowth in individuals
A mutations. (a–e) Subject a b c f
emity overgrowth with a
se tissue at ages 12 months
gressing to massive leg
upper-body adipose
which time above-knee
leg had been undertaken (c).
th at 35 years old.
howing overgrowth,
of the left foot and rotational d
oot. (f,g) Anterior (f) and h
ubject N7, showing leg
surgery and massive
oot, which was partially e
(h) and left (i) feet of subject
mited overgrowth confined to
. Informed consent to publish
ned from the identifiable
85
sequencing data c.1633G>A (p.Glu545Lys) variant being recurrent.
for de novo muta- The differences in mutation burden between HME cases prompte
De novo somatic mutations in components of the
(Supplementary us to examine this burden in anatomically defined brain regions i
PI3K-AKT3-mTOR pathway cause hemimega-
lencephaly
a
HME-1563 HME-1564 HME-1565
Right Left
Blood Brain
b
Lee et al., 2012, Nat.Genet., 44, 491 - 496.86
sequencing data c.1633G>A (p.Glu545Lys)
counts countsvariant being recurrent.
counts counts allele (%)
for de novo muta- The differences in mutation burden between
47 HME 16% cases prompte
De
PIK3CA
(Supplementary
novo somatic
c.1633G>A (HME-1573)
mutations
0
us to examine 0this burden
AKT3 c.49C>T (HME-1565)
121
in components
9
49 in anatomically
9
of
defined
23
the
brain
28% regions i
PI3K-AKT3-mTOR
MTOR c.4448C>T (HME-1563)
pathway
0 298
cause
17
hemimega-
159 9.7%
lencephaly
a c PIK3CA c.1633G>A (p.Glu545Lys) AKT3 c.49C>T (p.Glu17Lys) MTOR c.4448C>T (p.Cys1483Tyr)
HME-1563(HME-1573) HME-1564(HME-1565) HME-1565(HME-1563)
Blood Brain Blood Brain Blood Brain
A (0%) G (100%) A (36.6%) G (63.4%) G (100%) A (0%) G (59.6%) A (40.4%) T (0%) C (100%) T (8.1%) C (91.9%)
80 60 10 10 10 10
70 50 8 8 8
60 8
40
Intensity
50 6 6 6 6
40 30
30 4 4 4 4
20
20 2 2 2 2
10 10
0 0 0 0 0 0
Right
5,950 6,000 5,950 Left6,000 6,950 7,000 6,950 7,000 5,450 5,500 5,450 5,500
Mass
HME-1573 HME-1855 HME-1916
Blood Brain
b
Lee et al., 2012, Nat.Genet., 44, 491 - 496.87
6–30% in parietal, cen- family by binding to the pleckstrin homology (PH) domain. A
y, in HME-1563,
De novo where family proteins
somatic mutationscan directly phosphorylate the
in components ofmTOR
the protein, wh
ct regionsPI3K-AKT3-mTOR
of the central is the product of the MTOR
pathway cause The identification of de novo m
gene.hemimega-
rden to be quite variable, tions in these three genes, which are central to the mTOR pathwa
lencephaly
ion. These data indicate evidence that disrupted signaling underlies HME.
a Orbital
A (25.0%) G (75.0%)
Frontal
A (36.0%) G (64.0%)
80 25
HME-1573 (PIK3CA) 70 20
60
Intensity
50 15
40
Orb 30 10
20 5
10
0 0
Fr
5,950 6,000 5,950 6,000
b Parietal
G (73.1%) A (26.9%)
Central operculum
Lee et al., 2012,GNat.Genet.,
(69.6%) 44, 491
A (30.4%)
- 496.88
HME-1565 (AKT3) 50
50
Somatic mosaicism for activating
mutations in the PIK3CA gene
! Somatic mosaicism for activating mutations in PIK3CA
[OMIM 171834] has been associated with a variety of
asymmetrical overgrowth syndromes, including fibroadipose
hyperplasia, CLOVES syndrome [OMIM 612918],
segmental overgrowth affecting muscle and fat, and
megalencephaly phenotypes such as hemimegalencephaly
(HME) and megalencephaly-capillary malformation-
polymicrogyria syndrome (MCAP) [OMIM 602501].
Fertilized egg Gestation Infancy Childhood Adulthood Early clonal Benign Early invasive Late invasive Chemotherapy-
resistant
expansion tumour cancer cancer recurrence
Intrinsic
mutation processes Environmental
and lifestyle exposures Mutator
Passenger mutation phenotype Chemotherapy
Driver mutation
Chemotherapy
resistance mutation 1–10 or more
driver mutations
lineage of mitotic cell divisions from the fertilized egg to a cancer other processes, for example DNA repair defects, m
hin a cancer showing the timing of the somatic mutations the mutational burden. Passenger mutations do not have a
e cancer cell and the processes that contribute to them. cancer cell, but driver mutations will cause a clonal expansi
y be acquired while the cell lineage is phenotypically normal, chemotherapy can be associated with resistance mutations
the intrinsic mutations acquired during normal cell division predate the initiation of treatment.
of exogenous mutagens. During the development of the
Stratton et al., 2009, Nature, 458, 719 - 724.91
Comprehensive catalogue of somatic mutations
from a malignant melanoma genome
31 Somatic rearrangements
92
! At age of 15 years the average somatic cell will have
acquired at least 10-7 to 10-6 per coding nucleotide.
» 100 to 1000 mutations per non-replicating diploid cell.
» Proliferative cells (e. g. intestinal epithelium, epidermis) could
contain 1000 to 10 000 mutations.
! The intestinal epithelium of 60 years old person is
expected to harbour > 109 independent mutations. This
implies that nearly every genomic site has acquired a
mutation in at least one cell in this single organ.
Lynch 2010, Proc. Natl. Acad. Sci. USA, 107, 961 - 968. 93
Causes of death in the USA, 1900 - 2010
50 6 6 6 6
omatic genomebrain-blood paired (SGV).
variations samples. Mut,
Themutation;
two headed arrows 30 are
40 30
4 4 4 4
20
A
ref, reference. (c) Mass spectrometry validation 20 2
eant to suggest complex reciprocal interactions between 10
of mutations. Wild-type sequences (blue) and
them. that had been present on the left side of her trunk since birth. She had no
4-year-old
10 girl presented 2for evaluation of cutaneous nodules 2Dong-Lai Ma, M.D.,2Ph.D.
0 0 0 0 0Peking Union Medical College
0 Hospital
rom Sgaramella & Astolfi [39], with permission.
de novo mutations (red) are correlated with 5,950
history of seizures or developmental delay, and there was no family history Beijing, China
6,000 5,950 6,000 6,950 7,000 6,950 7,000 5,450 5,500 5,450 5,500
of similar cutaneous findings. Physical examination revealed numerous soft, non- mdonglai@sohu.com
results from next-generation sequencing. Mass distributed across
tender papules and nodules between 2 and 12 mm in diameter,
the left upper abdomen (Panel A) and wrapping around to the left back (Panels B Jin Hu, M.D.
ossible; representative cells should derive from tissuesand C). The remainder of the physical examination was unremarkable; axillary Affiliated Children’s Hospital
95
freckles, café au lait macules, and Lisch nodules were not observed. Results of a Beijing, China
DIGNUM MEMORIA
1. During each cell division new allelic variants are always
produced.
2. Huge majority of new allelic variants doesn’t influence cell’s
function as they
1. appear in regions containing no genes or introns;
2. doesn’t change significantly function of proteins which they
encode;
3. cause death of the cell.
3. In rare cases new allelic variants change properties of proteins
which they encode and this results in human pathology.
4. Somatic allelic variants can’t be transferred to the next
generations.
5. Severity of symptoms is determined by localization and number
of cells harbouring pathogenic allelic variants.
‹#›
Germ - line mutations
97
Germ - line mutations
REAL Genetics starts here!
98
Clinical,L Ehistological
TTERS and molecular
analysesa of nevus sebaceous Figure 1 Clinical, histological and
(a) Nevus sebaceous presenting a
plaque on the scalp. (b) Histopath
(from subject no. 52) comprise ep
sebaceous and apocrine glands, a
is present at the left and right ma
(c) Sanger sequencing chromatog
(left) and nevus sebaceous (right)
arrowhead indicates a c.37G>C p
Life-threatening complications
Life-threatening complications
Cardiac arrhythmia
Hypertrophic cardiomyopathy
Cardiac
Malignancy arrhythmia
Hypertrophic cardiomyopathy
Malignancy
OMIM #218040
ults and, for the fourth image on the first panel, Rick Guidotti/Positive Exposure. 100
Costello Syndrome Professional Advisory Board
Costello syndrome
OMIM #218040
101
Costello Syndrome Professional Advisory Board
Diagnostic methods for somatic and
germ-line mosaicism
a Hypothetical pedigree of somatic mosaicism b Hypothetical pedigree of germ-line mosaicism
WT
Blood
MUT
WT
A WT Sperm
Blood MUT
MUT
rder
is WT Normal
me skin
MUT
se.
s
ly in WT Abnormal
MUT skin
nd
Figure 2 | Diagnostic methods for somatic and germ-line mosaicism. a | Hypothetical pedigree of SEGMENTAL
NEUROFIBROMATOSIS TYPE I and (below) molecular analysis showing somatic mosaicism. The three-generation pedigree illustrates the
occurrence of a sporadic mutation (shown in red) in a second-generation male (represented as squares) manifested as a café-au-lait
skin lesion that is typical of neurofibromatosis type I (NFI). Although this disorder is typically inherited as an autosomal-dominant trait,
e
none of the offspring of the affected individual show the abnormality. Moreover, molecular
Youssoufian analysis
& Pyeritz reveals
2002, a putative
Nat. deletion
Rev. Genet., 3,(MUT)
748 - 758.
self 102
in the NF1 gene in DNA obtained from the abnormal skin of the affected patient. By contrast, only wild-type (WT) DNA is noted in
Mutation rate in germline cells
! Base substitution
» 1.1 - 1.7 x 10-8 per generation
! Indels
» 0.9 - 0.14 x 10-9 per site per generation
! Copy number variations
» 0.16 per haploid genome per generation
• 4 gonial and 2
meiotic divisions
108
! Number of chromosome replications from the zygote to
a sperm produced by man at age T is
- NT = 30 + 23(T - 15) + 5
20 150
30 380
45 725
110
Event Frequency Reference
111
Paternal age effect mutations
114
Crow 2006, J. Radiat. Res., 47 Sup.B, B75 - B82. 115
Mutation levels at the FGFR3 K650 codon in
sperm from 78 men (aged 22.1-73.9 years)
Figure 3 | Relative frequency of de novo achondroplasia and Apert syndrome for different paternal ages. The ordinate is the
ratio of the observed number of mutations (O) to the number expected (E), if all paternal ages are associated with the same frequency
of mutation. The blue line gives the actual data; the red line is the best-fitting exponential curve. (Figure adapted from REF. 4.)
much higher (at least 10%), with most dying very early stand out. Essentially all the mutations occur in males
Crow 2000, Nat. Rev. Genet., 1, 40 - 47.
in the prenatal period. For trisomy 21, 93% of 436 infor- and the paternal age dependence is strong. Other traits117
onality
escents/Adults
classic facial features
often curly hair Astolfi et al.
bromata
apilloma
eratosis, hyperpigmentation
ature
and orthopedic problems
velopmental delay) / MR
ntal retardation)
credits go to the parents of the above children and adults and, for the fourth image on the first panel, Rick Guidotti/Posi
‹#›
Diseases discussed in this lecture
‹#›
Glossary
‹#›
Glossary
124