Exemplos de análise
genética
(não biométrica)
Teste
χ
2, estatística Z, árvores genealógicas
# A causa é genética?
# Se é genética:
< Classes fenotípicas, ou
< Variação contínua?
P Capítulo 8
# Podem realizar-se cruzamentos
controlados, ou recorre-se a
genealogias?
Trabalho de detetive
Desenvolver e testar hipóteses sobre a genética duma
variação fenotípica
# Obtida uma geração segregante (selfing ou
testcross
), ajustar as proporções previstas
pelas leis de Mendel
< Teste χ
2’
G
i(obs
i– esp
i)
2/esp
i# Se a hipótese nula não é rejeitada:
< Cruzamentos para verificação
# Se é rejeitada:
< Diferentes proporções (ou seja, outra hipótese)
< Violação das leis de Mendel (letalidade, selecção
a nível gamético, ligação...)
Cruzamentos controlados
χ
k i k i i iobs
esp
esp
−1=
=−
2 1 2Σ
(
)
Teste χ
2
# Hipóteses principais
(na espécie humana):
< Dominante vs. Recessivo;
< Autossómico vs.
heterossómico X
# Outras hipóteses:
< Interacções entre
não-alelos, efeito materno, etc.
< Mais que um locus
< Heterossómico Y
< Mitocondrial
Genealogias
Gatos
Tigre cinzento
x
Uniforme canela
Tigre cinzento
F
1:
F
2:
Tigre cinzento
Tigre canela
Uniforme canela
Uniforme melânico
26
13
6
3
9:3:3:1 L P = 42%
A: tigre a: uniforme
B: com eumelanina b: sem eumelanina
AaBb
A-B-A-bb
aaB-aabb
Ratinhos
Preto
x
Branco às pintas
Preto
F
1:
F
2:
Preto
Castanho
Branco às pintas
178
76
66
9:3:4 L P = 87%
B: preto b: castanho
S: uniforme s: às pintas
BbSs
B-S---ss
bbS-Castanhas
18
Pretas
58
{
9:3:3:1 L P = 83%
B-ss
bbss
Ratinhos
Cinzento
x
Albino
Preto
F
1:
F
2:
Preto
Cinzento
Albino
125
51
64
2:1:1 L P = 40%
Pp
Pp
PP
pp
P: cinzento; p: albino (sobredominância: preto)
C: Normal c: albino
D: Normal d: diluído
CcDd
C-D-C-dd
cc--9:3:4 L P = 41%
Milho
folhas de listas brancas
folhas brilhantes
x
plântula amarelada
F
1:
normais
F
2:
normais
listas, brilho
amareladas
listas, brilho, amareladas
70
19
24
5
9:3:3:1 L P = 67%
e ainda:
1
1
listas
brilho
a: listas
b: brilho
c: amareladas
aabbCC
AABBcc
ABC
abC
ABc
ab c
aB
Ab
C
C
ab
AB
C
c
L r
.2%
Figure 1
A three-generation Chinese pedigree with aminoglycoside-induced and nonsyndromic hearing impairment
Hearing impaired individuals are indicated by filled symbols. Arrow denotes proband. Asterisks denote individuals who had a history of exposure to aminoglycosides.
Autismo
* comunicação verbal limitada ou ausente
* falta de interação social recíproca ou capacidade de resposta
* padrões de interesses e comportamento restritos, estereotipados e ritualizados razão entre sexos 4-10 m : 1 f
frequentemente incluem-se nas análises as doenças do espetro autista (ASD:
autism spectrum disorders), como a doença de Asperger
21 same-sex twin pairs 11 MZ + 10 DZ at least 1 had infantile autism: 36% concordance [autismo] among the MZ twins [4 pares] and no concordance among the DZ twins; for cognitive abnormalities 82% for MZ pairs and 10% for DZ pairs.
[em 12 dos 17 não-concordantes] 'a biologic hazard liable to cause brain damage was identified. The authors
concluded that brain injury in infancy may lead to autism on its own or in combination with a genetic predisposition'
OMIM %209850
27 same-sex pairs MZ + 20 DZ twins: 60% MZ concordant for autism compared to 0% DZ. When they considered a broader spectrum of related cognitive or social abnormalities, 92% MZ concordant compared to 10% DZ. The rapid fall off of concordance in DZ suggested a multilocus, epistatic model. In the nonconcordant
Autismo
40 pairs of twins: concordance rate for autism of 23.5% in dizygotic twins (4 of 17 pairs) and 95.7% in monozygotic twins (22 of 23 pairs). Classic segregation analysis yielded a maximum likelihood estimate of the segregation ratio of 0.19 +/-0.07 (DZ) --> autosomal recessive inheritance
Utah kinship for all possible pairs of autistic subjects: 86 autistic subjects were linked to the Utah Genealogical Database; 50 replicate sets of matched control subjects (86 members in each set) were drawn randomly from the database, and the average kinship coefficient was computed for all possible pairs of individuals in each set.
When kinship was analyzed by specific degrees of relationship, it was shown that the familial aggregation of autism is confined exclusively to sib pairs and does not extend to more remote degrees of relationship. This finding indicates that a single-gene model is unlikely to account for most cases of autism.
Of 166 affected sib pairs, 30 (12 MZ, 17 DZ, and 1 of unknown zygosity) were twin pairs (in a similarly ascertained sample of individuals with type I diabetes, there was no deviation from expected values); risk factors
related to fetal development or other factors, genetic or nongenetic, in the parents may contribute to autism.
Autismo
Confirmed de novo CNVs were significantly associated with autism (P = 0.0005). Such CNVs were identified in 12 out of 118 (10%) of patients with sporadic autism, in 2 out of 77 (3%) of patients with an affected first-degree relative, and in 2 out of 196 (1%) of controls. Most de novo CNVs were smaller than microscopic resolution. Affected genomic regions were highly heterogeneous and included mutations of single genes.
OMIM %209850
familial risk of autism in a population-based cohort of 2,049,973 Swedish children born from 1982 to 2006: 37,570 twin pairs; 2,642,064 full-sib pairs; 432,281 maternal and 445,531 paternal half-sib pairs; and 5,799,875 cousin pairs.
Diagnoses of ASD to December 31, 2009 were ascertained. Exposure refers to the presence or absence of autism in a sib.
In the sample, 14,516 children were diagnosed with ASD, of whom 5,689 had autistic disorder. The relative recurrence risk (RRR) and rate per 100,000 person-years was estimated to be 153.0 (MZ), 8.2 (DZ), 10.3 (full sibs), 3.3 (maternal half sibs), 2.9 (paternal half sibs), 2.0 (cousins). The RRR pattern was similar for autistic disorder but of slightly higher magnitude
... concluded that among children in Sweden, the individual risk of ASD and autistic disorder increased with increasing genetic relatedness.
