Mycobacterium tuberculosis complex genetic diversity: mining the fourth international spoligotyping database (SpolDB4) for classification, population genetics and epidemiology.
BACKGROUND
The Direct Repeat locus of the Mycobacterium tuberculosis complex (MTC) is a member of the CRISPR (Clustered regularly interspaced short palindromic repeats) sequences family. Spoligotyping is the widely used PCR-based reverse-hybridization blotting technique that assays the genetic diversity of this locus and is useful both for clinical laboratory, molecular epidemiology, evolutionary and population genetics. It is easy, robust, cheap, and produces highly diverse portable numerical results, as the result of the combination of (1) Unique Events Polymorphism (UEP) (2) Insertion-Sequence-mediated genetic recombination. Genetic convergence, although rare, was also previously demonstrated. Three previous international spoligotype databases had partly revealed the global and local geographical structures of MTC bacilli populations, however, there was a need for the release of a new, more representative and extended, international spoligotyping database.


RESULTS
The fourth international spoligotyping database, SpolDB4, describes 1939 shared-types (STs) representative of a total of 39,295 strains from 122 countries, which are tentatively classified into 62 clades/lineages using a mixed expert-based and bioinformatical approach. The SpolDB4 update adds 26 new potentially phylogeographically-specific MTC genotype families. It provides a clearer picture of the current MTC genomes diversity as well as on the relationships between the genetic attributes investigated (spoligotypes) and the infra-species classification and evolutionary history of the species. Indeed, an independent Naïve-Bayes mixture-model analysis has validated main of the previous supervised SpolDB3 classification results, confirming the usefulness of both supervised and unsupervised models as an approach to understand MTC population structure. Updated results on the epidemiological status of spoligotypes, as well as genetic prevalence maps on six main lineages are also shown. Our results suggests the existence of fine geographical genetic clines within MTC populations, that could mirror the passed and present Homo sapiens sapiens demographical and mycobacterial co-evolutionary history whose structure could be further reconstructed and modelled, thereby providing a large-scale conceptual framework of the global TB Epidemiologic Network.


CONCLUSIONS
Our results broaden the knowledge of the global phylogeography of the MTC complex. SpolDB4 should be a very useful tool to better define the identity of a given MTC clinical isolate, and to better analyze the links between its current spreading and previous evolutionary history. The building and mining of extended MTC polymorphic genetic databases is in progress.
Brudey
Karine
K
Unité de la Tuberculose et des Mycobactéries, Institut Pasteur de Guadeloupe, Guadeloupe.
Driscoll
Jeffrey R
JR
Rigouts
Leen
L
Prodinger
Wolfgang M
WM
Gori
Andrea
A
Al-Hajoj
Sahal A
SA
Allix
Caroline
C
Aristimuño
Liselotte
L
Arora
Jyoti
J
Baumanis
Viesturs
V
Binder
Lothar
L
Cafrune
Patricia
P
Cataldi
Angel
A
Cheong
Soonfatt
S
Diel
Roland
R
Ellermeier
Christopher
C
Evans
Jason T
JT
Fauville-Dufaux
Maryse
M
Ferdinand
Séverine
S
Garcia de Viedma
Dario
D
Garzelli
Carlo
C
Gazzola
Lidia
L
Gomes
Harrison M
HM
Guttierez
M Cristina
MC
Hawkey
Peter M
PM
van Helden
Paul D
PD
Kadival
Gurujaj V
GV
Kreiswirth
Barry N
BN
Kremer
Kristin
K
Kubin
Milan
M
Kulkarni
Savita P
SP
Liens
Benjamin
B
Lillebaek
Troels
T
Ho
Minh Ly
ML
Martin
Carlos
C
Martin
Christian
C
Mokrousov
Igor
I
Narvskaïa
Olga
O
Ngeow
Yun Fong
YF
Naumann
Ludmilla
L
Niemann
Stefan
S
Parwati
Ida
I
Rahim
Zeaur
Z
Rasolofo-Razanamparany
Voahangy
V
Rasolonavalona
Tiana
T
Rossetti
M Lucia
ML
Rüsch-Gerdes
Sabine
S
Sajduda
Anna
A
Samper
Sofia
S
Shemyakin
Igor G
IG
Singh
Urvashi B
UB
Somoskovi
Akos
A
Skuce
Robin A
RA
van Soolingen
Dick
D
Streicher
Elisabeth M
EM
Suffys
Philip N
PN
Tortoli
Enrico
E
Tracevska
Tatjana
T
Vincent
Véronique
V
Victor
Tommie C
TC
Warren
Robin M
RM
Yap
Sook Fan
SF
Zaman
Khadiza
K
Portaels
Françoise
F
Rastogi
Nalin
N
Sola
Christophe
C
D019295:Computational Biology; D016208:Databases, Factual; D005828:Genetics, Population; D009169:Mycobacterium tuberculosis / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D010802:Phylogeny; D011110:Polymorphism, Genetic; D012703:Serotyping; D014376:Tuberculosis / Q000453:epidemiology*