Tigers academy graduates Steward and Heyes are among eight uncapped players in the team selected by Eddie Jones, with Genge named as vice-captain.
Genge and Heyes are named either side of Sale Sharks hooker Curtis Langdon.
Jones said: “Over the past three weeks our biggest message to the players is what an opportunity this is to show what they can do and make their mark with England.
“They’ve applied themselves as a group and worked very hard individually during this camp to reach their personal bests.
“Now it’s all about coming together as a team, gelling and putting in a good performance at the weekend.”
England versus USA is live on Channel 4, with coverage starting from 1.30pm. Kick-off at Twickenham Stadium is at 2.00pm on Sunday.
15 Freddie Steward (Leicester Tigers, uncapped)
14 Joe Cokanasiga (Bath Rugby, 9 caps)
13 Henry Slade (Exeter Chiefs, 38 caps)
12 Ollie Lawrence (Worcester Warriors, 6 caps)
11 Max Malins (Saracens, 7 caps)
10 Marcus Smith (Harlequins, uncapped)
9 Harry Randall (Bristol Bears, uncapped)
1 Ellis Genge (Leicester Tigers, 28 caps)
2 Curtis Langdon (Sale Sharks, uncapped)
3 Joe Heyes (Leicester Tigers, uncapped)
4 Josh McNally (Bath Rugby, uncapped)
5 Charlie Ewels (Bath Rugby, 21 caps)
6 Lewis Ludlow (C) (Gloucester Rugby, uncapped)
7 Sam Underhill (Bath Rugby, 22 caps)
8 Callum Chick (Newcastle Falcons, uncapped)
16 Jamie Blamire (Newcastle Falcons, uncapped)
17 Beno Obano (Bath Rugby, 1 cap)
18 Trevor Davison (Newcastle Falcons, uncapped)
19 Ted Hill (Worcester Warriors, 1 cap)
20 Ben Curry (Sale Sharks, uncapped)
21 Lewis Ludlam (Northampton Saints, 8 caps)
22 Dan Robson (Wasps, 12 caps)
23 Jacob Umaga (Wasps, uncapped)