banner
Дом / Новости / Генотип АВО изменяет микробиоту кишечника, регулируя уровень GalNAc у свиней.
Новости

Генотип АВО изменяет микробиоту кишечника, регулируя уровень GalNAc у свиней.

Sep 06, 2023Sep 06, 2023

Nature, том 606, страницы 358–367 (2022 г.) Процитировать эту статью

22 тыс. доступов

33 цитаты

92 Альтметрика

Подробности о метриках

Состав кишечного микробиома значительно варьируется у разных людей и коррелирует со здоровьем1. Понимание того, в какой степени и каким образом генетика хозяина способствует этой изменчивости, имеет важное значение, однако оказалось трудным, поскольку лишь немногие ассоциации были воспроизведены, особенно у людей2. Здесь мы изучаем влияние генотипа хозяина на состав кишечной микробиоты в большой мозаичной популяции свиней. Мы показываем, что в условиях повышенного генетического разнообразия и однородности окружающей среды состав микробиоты и обилие специфических таксонов передаются по наследству. Мы картировали локус количественных признаков, влияющий на численность видов Erysipelotrichaceae, и показываем, что это вызвано делецией 2,3 т.п.н. в гене, кодирующем N-ацетил-галактозаминил-трансферазу, которая лежит в основе группы крови АВО у людей. Мы показываем, что эта делеция представляет собой трансвидовой полиморфизм возрастом ≥3,5 миллионов лет при балансирующем отборе. Мы продемонстрировали, что он снижает концентрацию N-ацетилгалактозамина в кишечнике и тем самым снижает численность Erysipelotrichaceae, которые могут импортировать и катаболизировать N-ацетилгалактозамин. Наши результаты предоставляют очень убедительные доказательства влияния генотипа хозяина на численность специфических бактерий в кишечнике в сочетании с пониманием молекулярных механизмов, лежащих в основе этой ассоциации. Наши данные открывают путь к выявлению такого же эффекта в сельской местности.

Все больше признается, что всестороннее понимание физиологии и патологии организмов требует комплексного анализа хозяина и его многочисленной микробиоты1. У человека состав кишечной микробиоты связан с физиологическими и патологическими параметрами, включая холестерин ЛПВП, уровень глюкозы натощак и индекс массы тела2. У домашнего скота состав микробиома рубца связан с выработкой метана и эффективностью корма3. Эти корреляции отражают сложное взаимодействие между хозяином и микробиотой, которое может включать прямое (причинное) влияние микробиома на физиологию хозяина4. Некоторые фенотипы, коррелирующие с составом микробиоты, являются наследственными5,6. Это приводит к гипотезе, что генотип хозяина может частично определять состав микробиоты, которая, в свою очередь, может влиять на фенотип хозяина4. Это означает, что состав микробиоты частично наследуется. Хотя исследования на грызунах подтверждают это7, данные на людях менее убедительны. Первоначальные отчеты не выявили более высокого сходства микробиоты между монозиготными близнецами по сравнению с дизиготными близнецами, что позволяет предположить ограниченное влияние генотипа хозяина8. Более мощные исследования предоставили доказательства значительного влияния генетики хозяина на численность таксонов, особенно Christensenellaceae9. Локусы, лежащие в основе наследственности микробиоты, по-прежнему трудно идентифицировать у людей. Помимо вариантов, которые вызывают постоянную экспрессию лактазы (LCT) и связаны со снижением численности бифидобактерий, оказалось, что другие локусы GWAS трудно реплицировать2,10,11,12,13,14. Анализ более крупных групп людей необходим для лучшего понимания генетической архитектуры состава микробиоты.

Чтобы расшифровать генетическую архитектуру состава кишечной микробиоты у крупного всеядного животного с однокамерным желудком, мы сообщаем о создании мозаичной популяции свиней и продольной характеристике ее кишечной микробиоты. Мы наблюдали сильное влияние генотипа хозяина на состав микробиоты и идентифицировали локус, оказывающий большое влияние на численность конкретных таксонов, контролируя концентрацию N-ацетилгалактозамина в кишечнике и тем самым влияя на некоторые виды, которые используют этот метаболит в качестве источник углерода.

7,500) mosaic population by intercrossing the offspring of 61 F0 founders from four Chinese and four western breeds for more than 10 generations (Supplementary Table 1 and Extended Data Fig. 1). Animals were reared in uniform housing and feeding conditions. We analysed more than 200 phenotypes (pertaining to body composition, physiology, disease resistance and behaviour), obtained transcriptome, epigenome and chromatin interaction data from multiple tissues, and collected plasma metabolome and microbiome data in up to 954 F6 and 892 F7 animals. The F0 animals were whole-genome sequenced at an average depth of 28.4-fold, and the F6 and F7 animals were sequence at an average depth of 8.0-fold. We called genotypes at 23.8 million single-nucleotide polymorphisms (SNPs) and 6.4 million insertion–deletions (indels) with a minor allele frequency (MAF) of ≥0.03 (>1/100 bp). The nucleotide diversity (π) (that is, the proportion of nucleotide sites that differ between homologous sequences in two breeds) between two Chinese breeds and between two European breeds was similar to that between Homo sapiens and Homo neanderthalensis (~3 × 10−3)15, whereas the π between a Chinese and a European breed approached half of that between human and chimpanzee (~4.3 × 10−3)16. The proportion of the eight founder genomes in F6 and F7 ranged from 11.2% to 14.7% at the genome level, and from 4.9% to 22.1% at the chromosome level. The median number of variants in high linkage disequilibrium (LD) (r2 ≥ 0.9) with an index variant was 30, and the median maximal distance with a variant in high LD (r2 ≥ 0.9) was 54 kb (Extended Data Fig. 1)./p>5% were filtered out. Non-redundant MAGs were generated by dRep (v.2.3.2) at threshold of 99% average nucleotide identity (ANI)92./p>

2-fold higher in domestic pigs than in human populations, as previously reported111,112,113. Nucleotide diversities between Chinese founder breeds and between European founder breeds were ~3.6x10−3 and ~2.5x10−3, respectively, i.e. 1.44-fold and 1.25-fold higher than the respective within-breed π-values. These π-values are of the same order of magnitude as the sequence divergence between Homo sapiens and Neanderthals/Denosivans (~3x10−3, ref. 15). By comparison, π-values between Africans, Asians and Europeans are typically ≤ ~1x10−3 (ref. 109). The nucleotide diversity between Chinese and European breeds averaged ~4.3x10−3. This π-value is similar to the divergence between M. domesticus and M. castaneus114, and close to halve the ~1% difference between chimpanzee and human16. Note that Chinese and European pig breeds are derived from Chinese and European wild boars, respectively, which are thought to have diverged ~1 million years ago27, while M. domesticus and M. castaneus are thought to have diverged ≤ 500,000 years ago114. (d) Autosome-specific estimates of the genomic contributions of the eight founder breeds in the F6 and F7 generation. We used a linear model incorporating all variants to estimate the average contribution of the eight founder breeds in the F6 and F7 generation at genome and chromosome level56. At genome-wide level, the proportion of the eight founder breed genomes ranged from 11.2% (respectively 11.5%) to 14.1% (14.7%) in the F6 (F7) generations. At chromosome-specific level, the proportion of the eight founder breeds ranged from 6.7% (respectively 4.9%) to 20.7% (22.1%) in the F6 (F7) generations. The genomic contribution of the eight founder breeds in the F6 and F7 generation is remarkably uniform and close to expectations (i.e. 12.5%) both at genome-wide and chromosome-wide level, suggesting comparable levels of genetic diversity across the entire genome. This does not preclude that more granular examination may reveal local departures from expectations, or under-representation of incompatible allelic combinations at non-syntenic loci. (e-f) Indicators of achievable mapping resolution in the F6 generation: (e) Frequency distribution (density) of the number of variants in high LD (r2 ≥ 0.9) with an “index” variant (was computed separately for all variants considered sequentially as the “index”), corresponding to the expected size of “credible sets” in GWAS115. The red vertical line corresponds to the genome-wide median. The green vertical line corresponds to the mapping resolution achieved in this study for the ABO locus (see hereafter). (f) Frequency distribution (density) of the maximum distance between an index variant and a variant in high LD (r2 ≥ 0.9) with it, defining the spread of credible sets. Red and green vertical lines are as in (D)./p>95% of day 120 and 240 faeces and caecum content samples of both F6 and F7 generations, hence defined as core bacterial taxa. (b) The compositions of the porcine and human intestinal microbiota are closer to each other than either is to that of the mouse. Boxplots are as is Fig. 1c. The number of samples available for analysis were 1281 pigs, 106 humans and 6 mice. (c) Abundances (F6-F7 averages when available) of the 43 families represented in Fig. 1b in the seven sample types relative to the sample type in which they are the most abundant (red – blue scale). The families are ordered according to the sample type in which they are the most abundant. The colour-code for phyla is as in Fig. 1b. Columns are added for comparison with mouse and human. Mouse data are from Fig. 1 in Suzuki & Nachman116, and human data from Fig. 6 in Vuik et al117. P_I: proximal ileum, D_IL: distal ileum, C: caecum, CO: colon, RE: rectum, F: faeces. The families differing the most with regards to location-specific distribution between species include Helicobacteriaceae, Veillonellaceae, Lactobacillaceae and Streptocaccaceae./p> 10 MYA. It will be interesting to study larger numbers of warthog to see whether the same 2.3 kb deletion exists in this and other related species as well. (b) Alignment of ~900 base pairs of the O alleles of domestic pigs (Bamaxian), European and Asian wild boars, and Sus cebufrons demonstrating that these are identical-by-descent. The SINE element that is presumed to have mediated the recombinational event that caused to 2.3 kb deletion is highlighted in red. Context: To further support their identity-by-descent we aligned ~900 base pairs (centred on the position of the 2.3 kb deletion) of the O alleles of domestic pig, European and Asian wild boars and Sus cebifrons. The sequences were nearly identical further supporting our hypothesis. It is noteworthy that the old age of the “O” allele must have contributed to the remarkable mapping resolution (≤3 kb) that was achieved in this study. In total, 42 variants were in near perfect LD (r2 ≥ 0.9) with the 2.3 kb deletion in the F0 generation, spanning 2,298 bp (1,522 on the proximal side, and 762 on the distal side of the 2.3 kb deletion). This 2.3 kb span is lower than genome-wide expectations (17th percentile), presumably due to the numerous cross-overs that have accrued since the birth of the 2.3 kb deletion that occurred in the distant past. Yet the number of informative variants within this small segment is higher than genome-wide average of (57% percentile) also probably due at least in part to the accumulation of numerous mutations since the remote time of coalescence of the A and O alleles (see Fig. 1d in main text). (c) QQ plots for the effect of AO genotype on 150 phenotypes pertaining to meat quality, growth, carcass composition, hematology, health, and other phenotypes in the F6 and F7 generation. P-values were obtained using a mixed model followed by meta-analysis (weighted Z score) across the F6 and F7 generations as described in Methods. log-transformed p-values used for the QQ plot are nominal and two-sided. Context: Our findings in suidae are reminiscent of the trans-species polymorphism of the ABO gene in primates attributed to balancing selection26. The phenotype driving balancing selection remain largely unknown yet a tug of war with pathogens is usually invoked: synthesized glycans may affect pathogen adhesion, toxin binding or act as soluble decoys, while naturally occurring antibodies may be protective20,44. In humans, the O allele may protect against malaria118, E. Coli and Salmonella enteric infection119, SARS-CoV-142, SARS-CoV-243 and schistosomiasis120,121,122, while being a possible risk factor for cholera123, H. pylori124 and norovirus infection125. Whatever the underlying selective force, it appears to have operated independently in at least two mammalian branches (primates and suidae), over exceedingly long periods of time, and over broad geographic ranges, hence pointing towards its pervasive nature. To gain insights in what selective forces might underpin the observed balanced polymorphism, we tested the effect of porcine AO genotype on >150 traits measured in the F6 and F7 generations pertaining to carcass composition, growth, meat quality, hematological parameters, disease resistance and behaviour. No significant effects were observed when accounting for multiple testing, including those pertaining to immunity and disease resistance. (d) Expression profile of the AO gene in a panel of adult and embryonic porcine tissues (own RNA-Seq data)./p>