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The genomes of living lungfishes can inform on the molecular-developmental basis of the Devonian sarcopterygian fish–tetrapod transition. We de novo sequenced the genomes of the African (Protopterus annectens) and South American lungfishes (Lepidosiren paradoxa). The Lepidosirengenome (about 91 Gb, roughly 30 times the human genome) is the largest animal genome sequenced so far and more than twice the size of the Australian (Neoceratodus forsteri)1and African2lungfishes owing to enlarged intergenic regions and introns with high repeat content (about 90%). All lungfish genomes continue to expand as some transposable elements (TEs) are still active today. In particular, Lepidosiren’s genome grew extremely fast during the past 100 million years (Myr), adding the equivalent of one human genome every 10 Myr. This massive genome expansion seems to be related to a reduction of PIWI-interacting RNAs and C2H2 zinc-finger and Krüppel-associated box (KRAB)-domain protein genes that suppress TE expansions. Although TE abundance facilitates chromosomal rearrangements, lungfish chromosomes still conservatively reflect the ur-tetrapod karyotype. Neoceratodus’ limb-like fins still resemble those of their extinct relatives and remained phenotypically static for about 100 Myr. We show that the secondary loss of limb-like appendages in the Lepidosiren–Protopterusancestor was probably due to loss of sonic hedgehog limb-specific enhancers.

Hepatocellular carcinoma (HCC) is an inflammation-associated cancer arising from viral or non-viral etiologies including steatotic liver diseases (SLDs). Expansion of immunosuppressive myeloid cells is a hallmark of inflammation and cancer, but their heterogeneity in HCC is not fully resolved and might underlie immunotherapy resistance. Here, we present a high-resolution atlas of innate immune cells from patients with HCC that unravels an SLD-associated contexture characterized by influx of inflammatory and immunosuppressive myeloid cells, including a discrete population of THBS1+regulatory myeloid (Mreg) cells expressing monocyte- and neutrophil-affiliated genes. THBS1+Mregcells expand in SLD-associated HCC, populate fibrotic lesions, and are associated with poor prognosis. THBS1+Mregcells are CD163+but distinguished from macrophages by high expression of triggering receptor expressed on myeloid cells 1 (TREM1), which contributes to their immunosuppressive activity and promotes HCC tumor growth in vivo. Our data support myeloid subset-targeted immunotherapies to treat HCC.